6,5-bicyclic 5-HT2ar agonists and uses thereof

Abstract

The present disclosure relates to compounds useful for activating the 5-hydroxytryptamine 2A receptor (5-HT2AR), pharmaceutically acceptable compositions thereof, and methods of using said compounds and compositions.

Description

410095-003WQ (221371)6, 5- BICYCLIC 5-HT2AR AGONISTS AND USES THEREOFCROSS-REFERENCE TO RELATED APPLICATIONS

[0001] The application claims the benefit of priority to U.S. Provisional Application No. 63 / 699.519, filed September 26, 2024: U.S. Provisional Application No. 63 / 749,981, filed January 27, 2025; and U.S. Provisional Application No. 63 / 867,229, filed August 20, 2025; the contents of each of which are herein incorporated by reference.TECHNICAL FIELD OF THE INVENTION

[0002] The present invention relates to compounds and methods useful for activating the 5- hydroxytryptamine 2A receptor (5-HT2AR). The invention also provides pharmaceutically acceptable compositions comprising compounds of the present invention and methods of using said compositions in the treatment of various disorders.BACKGROUND OF THE INVENTION

[0003] Agonists of the 5-HT2AR may have potential as pharmacals for a variety of neurological diseases and disorders including, but not limited to, depression, anxiety, substance abuse, migraine headaches, and / or cluster headaches, and various somatic illnesses including, but not limited to, various inflammatory cardiovascular, and / or pain disorders. As such, 5-HT2AR agonists hold promise as therapeutic agents.SUMMARY OF THE INVENTION

[0004] The present application relates to compounds as agonists of 5-HT2AR, and methods of preparation and uses thereof. 5-HT2AR is a target of interest, owing to its role in psychiatric disorders including psychosis, depression, dyskinesia, and hallucination (Slocum et al., 2021). Although 5-HT2AR agonists have been developed, few are selective for this receptor over related subtypes, for example, the 5- HT2B receptor, a toxicology anti-target strongly implicated in serious side effects including drug-induced valvular heart disease.

[0005] It has now been found that compounds of this invention, and pharmaceutically acceptable compositions thereof, arc effective as agonists of 5-HT2AR. In some embodiments, the present disclosure provides a compound of formula I” :1BUSINESS.33535339.1or a pharmaceutically acceptable salt thereof, wherein each variable is as defined and described herein.

[0006] Compounds of the present invention, and pharmaceutically acceptable compositions thereof, are useful for treating a variety of diseases, disorders or conditions, associated with regulation of 5-HT2AR. Such diseases, disorders, or conditions include those described herein.

[0007] Compounds provided by this invention are also useful for the study of 5-HT2AR in biological and pathological phenomena; the study of intracellular signal transduction pathways occurring in bodily tissues; and the comparative evaluation of new 5-HT2AR modulators, in vitro or in vivo.DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS1. General Description of Certain Embodiments of the Invention:

[0008] Compounds of the present invention, and pharmaceutical compositions thereof, are useful as agonists of 5-HT2AR. In some embodiments, a provided compound, or a pharmaceutically acceptable salt thereof, is an agonist of 5-HT2AR.

[0009] In some embodiments, the present invention provides a compound of fonnula I”:or a pharmaceutically acceptable salt thereof, wherein each variable is as defined and described herein.

[0010] In another aspect, the present disclosure provides methods of treating and / or preventing a 5- HT2AR-mediated disorder in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a provided compound, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable composition thereof.

[0011] In another aspect, the present disclosure provides methods of treating and / or preventing a neurological disease, disorder, or condition in a patient in need thereof, comprising administering to the patient a provided compound, or a pharmaceutically acceptable salt thereof, or a pharmacally2BUSINESS.33535339.1acceptable composition thereof.

[0012] In another aspect, the present disclosure provides methods of activating the 5- hydroxytryptanunc 2A receptor (5-HT2AR) in a patient in need thereof, comprising administering to the patient a provided compound, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable composition thereof.

[0013] In another aspect, the present disclosure provides methods of increasing activation of a G protein signaling pathway associated with 5-HT2AR over a 0-arrestin signaling pathway associated with 5- HT2AR in a patient in need thereof, comprising administering to the patient a provided compound, or a pharmacally acceptable salt thereof, or a pharmacally acceptable composition thereof.

[0014] In another aspect, the present disclosure provides methods of selectively activating the 5- hydroxytryptamine 2A receptor (5-HT2AR) (e.g., over the 5-HT2B and / or 5-HT2C receptors) in a patient in need thereof, comprising administering to the patient a provided compound, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable composition thereof.

[0015] In another aspect, the present disclosure provides methods of treating and / or preventing a 5- HT2AR-mediated disorder in a patient in need thereof, and / or methods of activating the 5- hydroxytryptamine 2A receptor (5-HT2AR) in a patient in need thereof, comprising administering to the patient a provided compound, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable composition thereof, wherein the patient does not experience a hallucinogenic effect as a result of the activating or treating.2. Compounds and Definitions:

[0016] Compounds of the present invention include those described generally herein, and are further illustrated by the classes, subclasses, and species disclosed herein. As used herein, the following definitions shall apply unless otherwise indicated. For purposes of this invention, the chemical elements arc identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75thEd. Additionally, general principles of organic chemistry are described in “Organic Chemistry”, Thomas Sorrell, University Science Books, Sausalito: 1999, and “March’s Advanced Organic Chemistry”, 5thEd., Ed.: Smith, M.B. and March, J., John Wiley & Sons, New York: 2001, the entire contents of which are hereby incorporated by reference.

[0017] The term “aliphatic” or “aliphatic group”, as used herein, means a straight-chain (i.e., unbranched) or branched, substituted or unsubstituted hydrocarbon chain that is completely saturated or that contains one or more units of unsaturation, or a monocyclic hydrocarbon or bicyclic hydrocarbon that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic (also referred to herein as "carbocycle," “cycloaliphatic” or “cycloalkyl”), that has a single point of attachment3BUSINESS.33535339.1to the rest of the molecule. Unless otherwise specified, aliphatic groups contain 1-6 aliphatic carbon atoms. In some embodiments, aliphatic groups contain 1-5 aliphatic carbon atoms. In other embodiments, aliphatic groups contain 1-4 aliphatic carbon atoms. In still other embodiments, aliphatic groups contain 1-3 aliphatic carbon atoms, and in yet other embodiments, aliphatic groups contain 1-2 aliphatic carbon atoms. In some embodiments, “cycloaliphatic" (or “carbocycle" or “cycloalkyl") refers to a monocyclic Cs-Ce hydrocarbon that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic, that has a single point of attachment to the rest of the molecule. In some embodiments, a carbocyclic ring may be a 5-12 membered bicyclic, bridged bicyclic, or spirocyclic ring. A carbocyclic ring may include one or more oxo (=0) or thioxo (=S) substituent. Suitable aliphatic groups include, but are not limited to, linear or branched, substituted or unsubstituted alkyl, alkenyl, alkynyl groups and hybrids thereof such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl or (cycloalkyl)alkenyl.

[0018] As used herein, the term “bridged bicyclic” refers to any bicyclic ring system, i.e. carbocyclic or heterocyclic, saturated or partially unsaturated, having at least one bridge. As defined by IUPAC, a “bridge" is an unbranched chain of atoms or an atom or a valence bond connecting two bridgeheads, where a “bridgehead” is any skeletal atom of the ring system which is bonded to three or more skeletal atoms (excluding hydrogen). In some embodiments, a bridged bicyclic group has 7-12 ring members and 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfiir. Such bridged bicyclic groups are well known in the art and include those groups set forth below where each group is attached to the rest of the molecule at any substitutable carbon or nitrogen atom. Unless otherwise specified, a bridged bicyclic group is optionally substituted with one or more substituents as set forth for aliphatic groups. Additionally or alternatively, any substitutable nitrogen of a bridged bicyclic group is optionally substituted. Exemplary bridged bicyclics include:4BUSINESS.33535339.1

[0019] The term “lower alkyl” refers to a CM straight or branched alkyl group. Exemplar}’ lower alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and tert-butyl.

[0020] The term “heteroatom” means one or more of oxygen, sulfur, nitrogen, phosphorus, or silicon (including, any oxidized fonn of nitrogen, sulfur, phosphorus, or silicon; the quatemized form of any basic nitrogen or; a substitutable nitrogen of a heterocyclic ring, for example N (as in 3,4-dihydro-277-pyrrolyl), NH (as in pyrrolidinyl) or NR (as in N-substituted pyrrolidinyl)).

[0021] The tenn "unsaturated." as used herein, means that a moiety has one or more units of unsaturation.

[0022] As used herein, the term “bivalent Ci-s (or Ci-e) saturated or unsaturated, straight or branched, hydrocarbon chain”, refers to bivalent alkylene, alkcnylcnc, and alkynylcnc chains that arc straight or branched as defined herein.

[0023] The term “alkylene” refers to a bivalent alkyl group. An “alkylene chain” is a polymethylene group, i.e., -(CH2)n-, wherein n is a positive integer, preferably from 1 to 6, from 1 to 4, from 1 to 3, from 1 to 2, or from 2 to 3. A substituted alkylene chain is a polymethylene group in which one or more methylene hydrogen atoms are replaced with a substituent. Suitable substituents include those described below for a substituted aliphatic group.

[0024] The term “alkenylene” refers to a bivalent alkenyl group. A substituted alkenylene chain is a polymethylene group containing at least one double bond in which one or more hydrogen atoms are replaced with a substituent. Suitable substituents include those described below for a substituted aliphatic group.

[0025] As used herein, the term “cyclopropylcnyl” refers to a bivalent cyclopropyl group of the following structure:

[0026] Tire tenn “halogen” means F, Cl, Br, or I.

[0027] The term “aryl” used alone or as part of a larger moiety as in “aralkyl,” “aralkoxy.” or5BUSINESS.33535339.1410095-003WQ (221371)“aryloxyalkyl,” refers to monocyclic or bicyclic ring systems having a total of five to fourteen ring members, wherein at least one ring in the system is aromatic and wherein each ring in the system contains 3 to 7 ring members. The term "aryl" may be used interchangeably with the term “aryl ring.” In certain embodiments of the present invention, ‘‘aryl” refers to an arom atic ring system which includes, but not limited to. phenyl, biphenyl, naphthyl, anthracyl and the like, which may bear one or more substituents. Also included within the scope of the term “aryl,” as it is used herein, is a group in which an aromatic ring is fused to one or more non-aromatic rings, such as indanyl, phthalimidyl, naphthimidyl, phenanthridinyl, or tetrahydronaphthyl, and tire like. The term “arylenyl” refers to bivalent aryl groups (e.g., phenylenyl).

[0028] Tire terms “heteroaryl” and “hctcroar-,” used alone or as part of a larger moiety, c.g., “heteroaralkyl,” or “heteroaralkoxy,” refer to groups having 5 to 10 ring atoms, preferably 5, 6, or 9 ring atoms: having 6, 10, or 14 % electrons shared in a cyclic array; and having, in addition to carbon atoms, from one to five heteroatoms. The term “heteroatom” refers to nitrogen, oxygen, or sulfur, and includes any oxidized form of nitrogen or sulfur, and any quatemized form of a basic nitrogen. Heteroaryl groups include, without limitation, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tctrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, purinyl, naphthyridinyl, and pteridinyl. The terms “heteroaryl” and “heteroar-”, as used herein, also include groups in which a heteroaromatic ring is fused to one or more aryl, cycloaliphatic, or heterocyclyl rings, where the radical or point of attachment is on the heteroaromatic ring. Nonlimiting examples include indolyl, isoindolyl, benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzthiazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4 / 7 quinol iziny I. carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl. tetraliydroquinolinyl, tetrahydroisoquinolinyl. and pyrido[2,3-b]-l,4-oxazin-3(4H)-one. A heteroaryl group may be monocyclic, bicyclic, bridged bicyclic, or spirocyclic. The term “heteroaryl” may be used interchangeably with the terms “heteroaryl ring,” “heteroaryl group,” or “heteroaromatic,” any of which terms include rings that are optionally substituted. The term “heteroaralkyl” refers to an alkyl group substituted by a heteroaryl, wherein the alkyl and heteroaryl portions independently are optionally substituted. The temr “heteroarylenyl” refers to bivalent heteroaryl groups (e.g.. pyridylenyl).

[0029] As used herein, the terms “heterocycle,” “heterocyclyl,” “heterocyclic radical.” and “heterocyclic ring” are used interchangeably and refer to a stable 5- to 7-membered monocyclic or 7-10- membered bicyclic heterocyclic moiety that is either saturated or partially unsaturated, and having, in addition to carbon atoms, one or more, preferably one to four, heteroatoms, as defined above. When used in reference to a ring atom of a heterocycle, the term "nitrogen" includes a substituted nitrogen. As an example, in a saturated or partially unsaturated ring having 0-3 heteroatoms selected from oxygen, sulfur or nitrogen, the nitrogen may be N (as in 3.4-dihydro-2 / / pyrrolyl). NH (as in pyrrolidinyl), or+NR (as in6BUSINESS.33535339.1410095-003WQ (221371) ' substituted pyrrolidinyl).

[0030] A heterocyclic ring can be attached to its pendant group at any heteroatom or carbon atom that results in a stable structure and any of the ring atoms can be optionally substituted. Examples of such saturated or partially unsaturated heterocyclic radicals include, without limitation, tetrahydrofuranyl, tetrahydrothiophenyl pyrrolidinyl, piperidinyl, pyrrolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, oxazolidinyl, piperazinyL dioxanyl, dioxolanyL diazepinyl, oxazepinyl, thiazepinyl, morpholinyl, and quinuclidinyl. The terms ’‘heterocycle,” “heterocyclyl,” “heterocyclyl ring,” “heterocyclic group,” “heterocyclic moiety,” and “heterocyclic radical,” are used interchangeably herein, and also include groups in which a heterocyclyl ring is fused to one or more aryl, heteroaryl, or cycloaliphatic rings, such as indolinyl, 3H- indolyl. chromanyl, phenanthridinyl, or tetrahydroquinolinyl. In some embodiments, a heterocyclic ring may be a 5-12 membered bicyclic, bridged bicyclic, or spirocyclic ring. A heterocyclic ring may include one or more oxo (=0) or thioxo (=S) substituent. The term “heterocyclylalkyl” refers to an alkyl group substituted by a heterocyclyl, wherein the alkyl and heterocyclyl portions independently are optionally substituted.

[0031] As used herein, the temi “partially unsaturated” refers to a ring moiety that includes at least one double or triple bond. Hie term “partially unsaturated” is intended to encompass rings having multiple sites of unsaturation, but is not intended to include aryl or heteroaryl moieties. as herein defined.

[0032] As described herein, compounds of the disclosure may contain “substituted” moieties. In general, the term “substituted,” whether preceded by the term “optionally” or not, means that one or more hydrogens of the designated moiety of compounds are replaced with a suitable substituent. “Substituted”). Unless otherwise indicated, an “optionally substituted” group may have a suitable substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituent may be either the same or different at even- position. Combinations of substituents envisioned by this disclosure are preferably those that result in the formation of stable or chemically feasible compounds. The term “stable,” as used herein, refers to compounds that are not substantially altered when subjected to conditions to allow for their production, detection, and, in certain embodiments, their recovery, purification, and use for one or7BUSINESS.33535339.1more of the purposes disclosed herein.

[0033] Suitable monovalent substituents on a substitutable carbon atom of an “optionally substituted” group are independently halogen; (CI [?) >4F<OI -(CB I2)u4OR°: -0(CBl2)o 4R0, -0-(CBB2)OMC(0)OR°; - (CH2)CMCH(OR°)2; -(CH;)„ 4SR0; -(CHfr, 4 Ph. which may be substituted with R°; -(CH2)N40(CBl2)o iPh which may be substituted with R°; -CH=CHPh, which may be substituted with R°; -(CBI2)OMO(C1-I2)O 1- pyridyl which may be substituted with R°; -NO2; -CN; -N3; -(CH2)o^N(R°)2; -(CH2)0^N(R°)C(O)R°; - N(R°)C(S)R°; -(CH2)O4N(R°)C(0)NRO2; -N(RO)C(S)NR°2; -(CH2)OMN(R°)C(0)OR0;N(R°)N(R°)C(O)R°; -N(R°)N(R°)C(O)NR°2; -N(R°)N(R°)C(O)OR°; -(CH2)„4C(O)R°; -C(S)R°; - (CH2)(I 4C(O)OR°; -(CH2)OMC(0)SR°; -(CH2)NJZ’(O)OSIR°3: -(CH2)0MOC(O)R°; -OC(O)(CH2)„4S R°; - (CH2)CMSC(O)R°; -(CH2)OMC(0)NR02; -C(S)NRO2; -C(S)SR°; -SC(S)SR°, -(CH2)O4OC(O)NR°2; -C(O)N(OR°)R°; -C(O)C(O)R°; -C(O)CH2C(O)R°; -C(NOR°)R°; -(CH2)OMSSR°; -(CH2)O 4S(O)2R°; -(CH2)„4S(0)20RO; -(CH2)OMOS(0)2R°; -S(O)2NRO2; -(CH2)OMS(0)R°; -N(R°)S(O)2NRO2; - N(R°)S(O)2R°; -N(OR°)R°; -C(NH)NRO2; -(CI I2)o4P(0)2R°; -(CH2)OMP(0)R02; -(CH2)OMOP(0)R02; - (CH2)CMOP(O)(OR°)2; SiR0?,; -(CM straight or branched alkylene)O-N(R°)2; or -(CIM straight or branched alkylene)C(O)O-N(R°)2, wherein each R° may be substituted as defined below and is independently hydrogen, Ci-e aliphatic, -CH2Ph, 0(CB42)o iPh, -CH2-(5-6 membered heteroaryl ring), or a 5-6- membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, notwithstanding the definition above, two independent occurrences of R°, taken together with their intervening atom(s), form a 3-12-membered saturated, partially unsaturated, or aryl mono- or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, which may be substituted as defined below.

[0034] Suitable monovalent substituents on R° (or the ring fonned by taking two independent occurrences of R° together with their intervening atoms), are independently halogen. -(C142)o 2R*. -(CH2)O-2NR*2, -NO2, -SiR*3, -OSiR*3, -C(O)SR* -(CIM straight or branched alkylene)C(O)OR*, or - SSR* wherein each R* is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently selected from CIM aliphatic. -CH2PI1. -0(CBl2)o iPh, or a 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Suitable divalent substituents on a saturated carbon atom of R° include =0 and =S.

[0035] Suitable divalent substituents on a saturated carbon atom of an “optionally substituted” group include the following: =0. =S. =NNR*2, =NNHC(O)R*, =NNHC(O)OR*, =NNHS(O)2R*, =NR*. =NOR*, - O(C(R*2))2-3O-, or-S(C(R*2))2-3S-, wherein each independent occurrence of R* is selected from hydrogen,8BUSiNESS.33535339.1Ci-6 aliphatic which may be substituted as defined below, or an unsubstituted 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Suitable divalent substituents that are bound to vicinal substitutable carbons of an “optionally substituted” group include: -O(CR*2)2 3O-, wherein each independent occurrence of R* is selected from hydrogen, Ci-e aliphatic which may be substituted as defined below, or an unsubstituted 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0036] Suitable substituents on the aliphatic group of R* include halogen, -R*, -(haloR*), -OH, -OR’, -O(haloR*), -CN, -C(O)OH, -C(O)OR’, -NH2, -NHR*. -NR\ or -NO2, wherein each R* is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently Cu aliphatic, -CH2PI1. -0(CH2)o iPh, or a 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0037] Suitable substituents on a substitutable nitrogen of an “optionally substituted” group include - R:. -NR'2. -C(O)Rt, -C(O)OR\ -C(O)C(O)Rt, -C(O)CH2C(O)Rt, -S(O)2Rt, -S(O)2NR*2, -C(S)NRV - C(NH)NR12, or -N(R:)S(O)2R:; wherein each R' is independently hydrogen, Ci , aliphatic which may be substituted as defined below, unsubstituted -OPh, or an unsubstituted 5-6-membered saturated, partially unsaturated, or and ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, notwithstanding the definition above, two independent occurrences of R'. taken together with their intervening atom(s) form an unsubstituted 3-12-membered saturated, partially unsaturated, or ary l mono- or bicyclic ring having 0-4 hctcroatoms independently selected from nitrogen, oxygen, or sulfur.

[0038] Suitable substituents on the aliphatic group of R;are independently halogen, -R*, -(haloR*), - OH. -OR*, -O(haloR’). -CN. -C(O)OH, -C(O)OR*. -NH2, -NHR*. -NR’2, or -NO2, wherein each R* is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently Cw aliphatic, -CH2Ph, -O(CH2)0-iPh, or a 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0039] As used herein, the term "pharmacally acceptable salt" refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit / risk ratio. Pharmacally acceptable salts are well known in the art. For example, S. M. Berge et al., describe pharmaceutically acceptable salts in detail in J. Pharmacal Sciences, 1977, 66, 1-19, incorporated herein by reference. Pharmaceutically acceptable salts of the compounds of this invention include those derived from suitable inorganic and organic acids and bases.

[0040] Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N (C’i 4alkyl)4 salts. In some embodiments, the provided compounds are purified in salt form for9BUSINESS.33535339.1convenience and / or ease of purification, e.g., using an acidic or basic mobile phase during chromatography. Salts forms of the provided compounds formed during chromatographic purification are contemplated herein (e.g., diammonium salts) and are readily apparent to those having skill in the art.

[0041] Unless otherwise stated, structures depicted herein are also meant to include all isomeric (e.g., enantiomeric, diastereomeric, and geometric (or conformational)) forms of the structure; for example, the R and S configurations for each asymmetric center, Z and E double bond isomers, and Z and E conformational isomers. Therefore, single stereochemical isomers as well as enantiomeric, diastereomeric, and geometric (or conformational) mixtures of the present compounds are within the scope of the invention. Unless otherwise stated, all tautomeric forms of the compounds of the invention are within the scope of the invention. Additionally, unless otherwise stated, structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures including the replacement of hydrogen by deuterium or tritium, or the replacement of a carbon by a13C- or14C-enriched carbon are within the scope of this invention. Such compounds are useful, for example, as analytical tools, as probes in biological assays, or as therapeutic agents in accordance with the present invention

[0042] As used herein, the term about" refers to within 20% of a given value. In some embodiments, the term '‘about” refers to within 20%, 19%. 18%. 17%. 16%. 15%. 14%. 13%. 12%. 11%, 10%, 9%. 8%, 7%, 6%, 5%, 4%, 3%, 2%, or 1% of a given value.3. Description of Exemplary Embodiments:

[0043] In some embodiments, the present invention provides a compound of formula I”:or a pharmaceutically acceptable salt thereof, wherein:X1is N, NRla. or CR1:X2is N or CR2;X3is N or CR3;X4is N or CR4;X7is N or CR7;Xsis N, C, CH, or C-Ci-6 aliphatic;10BUSINESS.33535339.1X9is S, N, or NR9a; each — is independently a single or double bond, as valency allows, where one — between X9and X7or X7and X1is a double bond; each of R1, R2, R3, R4, or R7is independently selected from hydrogen, halogen, -CN, -OR3, -NR2, -C(O)R, -C(0)NR2, -C(O)OR, -NRC(O)R, -OC(O)R, or an optionally substituted group selected from C1-6 aliphatic, a 3 - to 8-membered saturated or partially unsaturated carbocyclyl or heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, phenyl, or a 5- to 6-membered heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur;R5is hydrogen or an optionally substituted group selected from Ci-e aliphatic or 3-to 8-membered saturated or partially unsaturated carbocyclyl or heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; each Rlaand R9ais independently hydrogen or optionally substituted Cve aliphatic; each R is independently hydrogen or optionally substituted Cue aliphatic; each R8is independently hydrogen, halogen, -CN, -OR, -NR2, or optionally substituted C1-6 aliphatic; or an R6and an R8group may be taken together to form an optionally substituted 3- to 8-membered saturated or partially unsaturated bridged or fused carbocyclyl or heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or two R8groups on the same atom may be taken together to form an optionally substituted 3- to 8- membered saturated or partially unsaturated spirocarbocyclyl or spiroheterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or two R8groups on different atoms may be taken together to form an optionally substituted 3- to 8- membered saturated or partially unsaturated bridged or fused carbocyclyl or heterocyclyl having 1 - 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur;R10is:Ring A is a saturated or partially unsaturated 4- to 6-membered monocyclic carbocyclyl, a saturated or partially unsaturated 7- to 8-membered bicyclic spirocyclic carbocyclyl. or a saturated or partially unsaturated 4- to 9-membered fused or bridged bicyclic carbocyclyl;Ring B is a saturated or partially unsaturated 4- to 6-membered monocyclic heterocyclyl having one or two nitrogen heteroatoms, a saturated or partially unsaturated 7- to 8-membered bicyclic spirocyclic heterocyclyl having one or two nitrogen heteroatoms, or a saturated or partially unsaturated 4- to 9- membered fused or bridged bicyclic heterocyclyl having one or two nitrogen heteroatoms;11BUSINESS.33535339.1L1is a covalent bond or an optionally substituted bivalent Cu saturated or unsaturated, straight or branched, hydrocarbon chain; each R is independently hydrogen or optionally substituted Ci-e aliphatic; and n is 0, 1, 2, 3, 4, 5, 6, 7, or 8.

[0044] In some embodiments, the present invention provides a compound of formula I':r or a pharmaceutically acceptable salt thereof, wherein:X1is N. NRla. or CR1;X2is N or CR2;X3is N or CR3;X4is N or CR4;X7is N or CR7;X9is S, N. or NR9a; each — is independently a single or double bond, as valency allows, where one — is a double bond; each of R1, R2, R3, R4, or R7is independently selected from hydrogen, halogen, -CN, -OR5, -NR , -C(O)R, -C(O)NR?, -C(O)OR, -NRC(O)R, -OC(O)R, or an optionally substituted group selected from Ci-e aliphatic, a 3 - to 8-mcmbcrcd saturated or partially unsaturated carbocyclyl or hctcrocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, phenyl, or a 5- to 6-membered heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur;R5is hydrogen or an optionally substituted group selected from Cue aliphatic or 3-to 8-membered saturated or partially unsaturated carbocyclyl or heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; each Rlaand R9ais independently hydrogen or optionally substituted Ci-e aliphatic; each R6and R8is independently hydrogen or optionally substituted Ci-6 aliphatic; or an R6and an R8group may be taken together to form an optionally substituted 3- to 8-membered saturated or partially unsaturated bridged or fused carbocyclyl or heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or two R8groups on the same atom may be taken together to form an optionally substituted 3- to 8- membered saturated or partially unsaturated spirocarbocyclyl or spiroheterocyclyl having 1-312BUSINESS.33535339.1heteroatoms independently selected from nitrogen, oxygen, or sulfur: or two R8groups on different atoms may be taken together to form an optionally substituted 3- to 8- membered saturated or partially unsaturated bridged or fused carbocyclyl or heterocyclyl having 1- 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur;R1CIis:each R is independently hydrogen or optionally substituted Ci-6 aliphatic; and ms 0. 1. 2, 3, 4. 5. 6, 7, or 8.

[0045] In some embodiments, the present invention provides a compound of formula I:or a pharmaceutically acceptable salt thereof, wherein:X1is N or CR1;X2is N or CR2;X3is N or CR3;X4is N or CR4; each of R1, R2, R3, R4, or R7is independently selected from hydrogen, halogen, -CN, -OR5, -NR2, -C(O)R, -C(O)NRj, -C(O)OR, -NRC(O)R, -OC(O)R, or an optionally substituted group selected from C1-6 aliphatic, a 3 - to 8-membered saturated or partially unsaturated carbocyclyl or heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, phenyl, or a 5- to 6-membered heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur;R5is hydrogen or an optionally substituted group selected from Ci-e aliphatic or 3-to 8-membered saturated or partially unsaturated carbocyclyl or heterocyclyl having 1-3 heteroatoms independently selected13BUSINESS.33535339.1from nitrogen, oxygen, or sulfur; each R6and Rsis independently hydrogen or optionally substituted Ci-6 aliphatic; or an R6and an R8group may be taken together to form an optionally substituted 3- to 8-membered saturated or partially unsaturated bridged or fused carbocyclyl or heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or two Rsgroups on the same atom may be taken together to form an optionally substituted 3- to 8- membered saturated or partially unsaturated spirocarbocyclyl or spiroheterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or two R8groups on different atoms may be taken together to form an optionally substituted 3- to 8- membered saturated or partially unsaturated bridged or fused carbocyclyl or heterocyclyl having 1- 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; each R is independently hydrogen or optionally substituted Ci-6 aliphatic; and n is 0, 1, 2, 3, 4, 5, 6, 7, or 8.

[0046] As defined above and described herein, X1is N, NRla, or CR1. In some embodiments, X1is N or CR1. In some embodiments, X1is NR1 a. In some embodiments, X1is N. In some embodiments, X1is CR1

[0047] As defined above and described herein, X2is N or CR2. In some embodiments. X2is N. In some embodiments, X2is CR2.

[0048] As defined above and described herein, X3is N or CR3. In some embodiments, X3is N. In some embodiments, X3is CR3.

[0049] As defined above and described herein, X4is N or CR4. In some embodiments. X4is N. In some embodiments, X is CR4.

[0050] As defined above and described herein, X7is N or CR7. In some embodiments, X7is N. In some embodiments, X7is CR7.

[0051] As defined above and described herein, X8is N, C, CH, or C-Ci-6 aliphatic. In some embodiments. Xsis CH or C-Ci-6 aliphatic. In some embodiments, X8is N or CH. In some embodiments, X8is N. In some embodiments, Xsis C. In some embodiments, X8is CH. In some embodiments, X8is C- Ci-6 aliphatic.

[0052] As defined above and described herein, X9is S, N, or NR9a. In some embodiments, X9is S. In some embodiments, X9is N. In some embodiments, X9is NR9a.

[0053] As defined above and described herein, each — is independently a single or double bond, as valency allows, where one — between X9and X7or X7and X1is a double bond.

[0054] In some embodiments, each — is independently a single or double bond, as valency allows,14BUSINESS.33535339.1where one — is a double bond. In some embodiments,;7;7embodiments, ' X1is ' X1In some embodiments,

[0055] As defined above and described herein, each of R1, R2, R3, R4, or R7is independently selected from hydrogen, halogen, -CN, -OR5, -NR2, -C(O)R, -C(O)NR , -C(O)OR, or an optionally substituted group selected from Cue aliphatic, a 3- to 8-membered saturated or partially unsaturated carbocyclyl or heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, phenyl, or a 5- to 6-membered heteroaiyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0056] In some embodiments, R1is selected from halogen, -CN, -OR5, -NR2, -C(O)R, -C(O)NR2, - C(O)OR, or an optionally substituted group selected from Ci-6 aliphatic, a 3- to 8-membered saturated or partially unsaturated carbocyclyl or heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, phenyl, or a 5- to 6-membered heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, R1is selected from hydrogen, halogen, - CN, -OR5, -NR?, -C(O)R, -C(O)NR?, -C(O)OR, or an optionally substituted group selected from Cue aliphatic, phenyl, or a 5- to 6-membered heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, R1is selected from halogen, -CN, -OR5, -NR2, -C(O)R, -C(O)NR2, -C(O)OR, or an optionally substituted group selected from Cue aliphatic, phenyl, or a 5- to 6- membered heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0057] In some embodiments, R1is hydrogen. In some embodiments, R1is halogen. In some embodiments, R1is fluoro. In some embodiments, R1is chloro. In some embodiments, R1is bromo. In some embodiments, R1is -CN.

[0058] In some embodiments, R1is -OR5. In some embodiments, R1is -OH. In some embodiments, R1is -OCH3. In some embodiments, R1is -OCH2CH3. In some embodiments, R1is -OCF3.

[0059] In some embodiments, R1is -NR2. In some embodiments, R1is -NH2. In some embodiments, R1is -NR2, wherein each R is independently C1-6 aliphatic.

[0060] In some embodiments, R1is -C(O)NR2. In some embodiments, R1is -C(O)NH2. In some embodiments, R1is -C(O)NR2, wherein each R is independently Cue aliphatic.

[0061] In some embodiments, R1is -C(O)OR. In some embodiments, R1is -C(O)OH. In some embodiments, R1is -C(O)OR, wherein R is C1-6 aliphatic.15BUSINESS.33535339.1

[0062] In some embodiments, R1is -NRC(O)R. In some embodiments, R1is -NHC(O)R. In some embodiments, R1is -NHC(O)R, wherein R is Ci-e aliphatic.

[0063] In some embodiments, R1is -OC(O)R. In some embodiments. R1is -OC(O)R, wherein R is Ci-6 aliphatic.

[0064] In some embodiments, R1is optionally substituted Cue aliphatic. In some embodiments, R1is Ci-6 aliphatic. In some embodiments, R1is methyl. In some embodiments, R1is ethyl. In some embodiments, R1is n-propyl. In some embodiments, R1is isopropyl. In some embodiments, R1is n -butyl. In some embodiments, R1is s-butyl. In some embodiments, R1is t-butyl.

[0065] In some embodiments. R1is Ci-6 aliphatic, optionally substituted with halogen or -OR°, wherein R° is hydrogen or Ci-6 aliphatic. In some embodiments, R1is Ci-6 aliphatic, optionally substituted with halogen. In some embodiments, R1is -CH2F. In some embodiments, R1is -CHF2. In some embodiments, R1is -CF3. In some embodiments, R1is -CH2CF3. In some embodiments, R1is Ci-c aliphatic, optionally substituted with -OR0, wherein R° is hydrogen or Ci-e aliphatic. In some embodiments, R1is - CH2OH.

[0066] In some embodiments, R1is an optionally substituted 3- to 8-membered saturated or partially unsaturated carbocyclyl or heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, R1is an optionally substituted 3- to 8-membered saturated or partially unsaturated carbocyclyl. In some embodiments, R1is an optionally substituted 3- to 6-mcmbcrcd saturated or partially unsaturated carbocyclyl. In some embodiments, R1is an optionally substituted cyclopropyl. In some embodiments, R1is an optionally substituted cyclobutyl. In some embodiments, R1is an optionally substituted cyclopentyl. In some embodiments, R1is an optionally substituted cyclohexyl. In some embodiments, R1is cyclopropyl. In some embodiments, R1is cyclobutyl. In some embodiments, R1is cyclopentyl. In some embodiments, R1is cyclohexyl.

[0067] In some embodiments, R1is an optionally substituted 3- to 8-membered saturated or partially unsaturated heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, R1is an optionally substituted 3- to 6-membered saturated or partially unsaturated heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur

[0068] In some embodiments, R1is an optionally substituted phenyl. In some embodiments, R1is an optionally substituted 5- to 6-membered heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0069] In some embodiments, R1is selected from hydrogen, halogen, -CN, or optionally substituted Ci-6 aliphatic.

[0070] In some embodiments, R2is selected from halogen, -CN, -OR’, -NR2, -C(O)R, -C(O)NR2, - C(O)OR, or an optionally substituted group selected from Ci-6 aliphatic, a 3- to 8-membered saturated or 16BUSINESS.33535339.1partially unsaturated carbocyclyl or heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, phenyl, or a 5- to 6-membered heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, R2is selected from hydrogen, halogen, - CN, -OR5, -NR2, -C(O)R, -C(0)NR2, -C(O)OR, or an optionally substituted group selected from C1-6 aliphatic, phenyl, or a 5- to 6-membered heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, R2is selected from halogen, -CN, -OR5, -NR2, -C(O)R, -C(0)NR2, -C(O)OR, or an optionally substituted group selected from C1-6 aliphatic, phenyl, or a 5- to 6- membered heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0071] In some embodiments, R2is hydrogen. In some embodiments, R2is halogen. In some embodiments, R2is fluoro. In some embodiments, R2is chloro. In some embodiments, R2is bromo. In some embodiments, R2is -CN.

[0072] In some embodiments, R2is -OR5. In some embodiments, R2is -OH. In some embodiments, R2is -OCH3. In some embodiments, R2is -OCH2CH3. In some embodiments, R2is -OCF3.

[0073] In some embodiments, R2is -NR2. In some embodiments, R2is -NH2. In some embodiments, R2is -NR2, wherein each R is independently C1-6 aliphatic.

[0074] In some embodiments, R2is -C(O)NR2. In some embodiments, R2is -C(O)NH2. In some embodiments, R2is -C(O)NR2, wherein each R is independently Ci-e aliphatic.

[0075] In some embodiments, R2is -C(O)OR. In some embodiments, R2is -C(O)OH. In some embodiments, R2is -C(O)OR, wherein R is C1-6 aliphatic.

[0076] In some embodiments, R2is -NRC(O)R. In some embodiments. R2is -NHC(O)R. In some embodiments, R2is -NHC(O)R, wherein R is C1.6 aliphatic.

[0077] In some embodiments, R2is -OC(O)R. In some embodiments, R2is -OC(O)R, wherein R is Ci .6 aliphatic.

[0078] In some embodiments, R2is optionally substituted Ci-6 aliphatic. In some embodiments, R2is C1-6 aliphatic. In some embodiments, R2is methyl. In some embodiments, R2is ethyl. In some embodiments, R2is n-propyl. In some embodiments, R2is isopropyl. In some embodiments, R2is n-butyl. In some embodiments, R2is s-butyl. In some embodiments, R2is t-butyl.

[0079] In some embodiments, R2is C1-6 aliphatic, optionally substituted with halogen or -OR°, wherein R° is hydrogen or C1-6 aliphatic. In some embodiments, R2is Ci-e aliphatic, optionally substituted with halogen. In some embodiments. R2is -CH2F. In some embodiments, R2is -CHF2. In some embodiments, R2is -CF3. In some embodiments, R2is -CH2CF3. In some embodiments, R2is Ci.g aliphatic, optionally substituted with -OR0, wherein R° is hydrogen or Ci-e aliphatic. In some embodiments, R2is - CH2OH.17BUSINESS.33535339.1

[0080] In some embodiments, R2is an optionally substituted 3- to 8-membered saturated or partially unsaturated carbocyclyl or heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, R2is an optionally substituted 3- to 8-mcmbcrcd saturated or partially unsaturated carbocyclyl. In some embodiments, R2is an optionally substituted 3- to 6-membered saturated or partially unsaturated carbocyclyl. In some embodiments, R2is an optionally substituted cyclopropyl. In some embodiments, R2is an optionally substituted cyclobutyl. In some embodiments, R2is an optionally substituted cyclopentyl. In some embodiments, R2is an optionally substituted cyclohexyl. In some embodiments, R2is cyclopropyl. In some embodiments, R2is cyclobutyl. In some embodiments, R2is cyclopentyl. In some embodiments, R2is cyclohexyl.

[0081] In some embodiments, R2is an optionally substituted 3- to 8-membered saturated or partially unsaturated heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, R2is an optionally substituted 3- to 6-membered saturated or partially unsaturated heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur

[0082] In some embodiments, R2is an optionally substituted phenyl. In some embodiments, R2is an optionally substituted 5- to 6-membered heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0083] In some embodiments, R2is selected from hydrogen, halogen, -CN, or optionally substituted Ci -s aliphatic.

[0084] In some embodiments, R3is selected from halogen, -CN, -OR5, -NR2, -C(O)R, -C(O)NR2, - C(O)OR, or an optionally substituted group selected from Ci-e aliphatic, a 3- to 8-membered saturated or partially unsaturated carbocyclyl or heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, phenyl, or a 5- to 6-membered heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, R3is selected from hydrogen, halogen, - CN, -OR5, -NR?, -C(O)R, -C(O)NR2, -C(O)OR, or an optionally substituted group selected from Cue aliphatic, phenyl, or a 5- to 6-membered heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, R3is selected from halogen, -CN, -OR5, -NR?, -C(O)R, -C(O)NR2, -C(O)OR, or an optionally substituted group selected from Ci-e aliphatic, phenyl, or a 5- to 6- membered heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0085] In some embodiments, R3is hydrogen. In some embodiments, R3is halogen. In some embodiments, R3is fluoro. In some embodiments, R3is chloro. In some embodiments, R3is bromo. In some embodiments, R3is -CN.

[0086] In some embodiments, R3is -OR5. In some embodiments, R3is -OH. In some embodiments, R3is -OCH3. In some embodiments, R3is -OCH2CH3. In some embodiments, R3is -OCF3.

[0087] In some embodiments, R3is -NR?. In some embodiments, R3is -NH2. In some embodiments,18BUSINESS.33535339.1R3is -NR:, wherein each R is independently Ci-6 aliphatic.

[0088] In some embodiments, R3is -C(O)NR2. In some embodiments, R3is -C(O)NH2. In some embodiments, R3is -C(O)NR2, wherein each R is independently Ci-g aliphatic.

[0089] In some embodiments, R3is -C(O)OR. In some embodiments, R3is -C(O)OH. In some embodiments. R3is -C(O)OR. wherein R is Ci-6 aliphatic.

[0090] In some embodiments, R3is -NRC(O)R. In some embodiments, R3is -NHC(O)R. In some embodiments, R3is -NHC(O)R, wherein R is Cue aliphatic.

[0091] In some embodiments, R3is -OC(O)R. In some embodiments. R3is -OC(O)R, wherein R is Ci-6 aliphatic.

[0092] In some embodiments, R3is optionally substituted Cue aliphatic. In some embodiments, R3is Cue aliphatic. In some embodiments, R3is methyl. In some embodiments, R3is ethyl. In some embodiments, R3is n-propyl. In some embodiments, R3is isopropyl. In some embodiments, R3is n -butyl. In some embodiments, R3is s-butyl. In some embodiments, R3is t-butyl.

[0093] In some embodiments. R3is Ci-6 aliphatic, optionally substituted with halogen or -OR°, wherein R° is hydrogen or Ci-6 aliphatic. In some embodiments, R3is Cue aliphatic, optionally substituted with halogen. In some embodiments, R3is -CH2F. In some embodiments, R3is -CHF2. In some embodiments, R3is -CF3. In some embodiments, R3is -CH2CF3. In some embodiments, R3is Ci.g aliphatic, optionally substituted with -OR0, wherein R° is hydrogen or Ci-6 aliphatic. In some embodiments, R3is - CH2OH.

[0094] In some embodiments, R3is an optionally substituted 3- to 8-membered saturated or partially unsaturated carbocyclyl or heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, R3is an optionally substituted 3- to 8-membered saturated or partially unsaturated carbocyclyl. In some embodiments, R3is an optionally substituted 3- to 6-membered saturated or partially unsaturated carbocyclyl. In some embodiments, R3is an optionally substituted cyclopropyl. In some embodiments, R3is an optionally substituted cyclobutyl. In some embodiments, R3is an optionally substituted cyclopentyl . In some embodiments, R3is an optionally substituted cyclohexyl. In some embodiments, R3is cyclopropyl. In some embodiments, R3is cyclobutyl. In some embodiments, R3is cyclopentyl. In some embodiments, R3is cyclohexyl.

[0095] In some embodiments, R3is an optionally substituted 3- to 8-membered saturated or partially unsaturated heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, R3is an optionally substituted 3- to 6-membered saturated or partially unsaturated heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur

[0096] In some embodiments, R3is an optionally substituted phenyl. In some embodiments, R3is an optionally substituted 5- to 6-membered heteroaryl having 1-3 heteroatoms independently selected from 19BUSINESS.33535339.1nitrogen, oxygen, or sulfur.

[0097] In some embodiments, R3is selected from hydrogen, halogen, -CN, or optionally substituted Ci-6 aliphatic.

[0098] In some embodiments, R4is selected from halogen, -CN, -OR5, -NR2, -C(O)R, -C(O)NR2, - C(O)OR, or an optionally substituted group selected from C1-6 aliphatic, a 3- to 8-membered saturated or partially unsaturated carbocyclyl or heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, phenyl, or a 5- to 6-membered heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, R4is selected from hydrogen, halogen, - CN, -OR5, -NR2, -C(O)R, -C(O)NR2, -C(O)OR, or an optionally substituted group selected from C1-6 aliphatic, phenyl, or a 5- to 6-membered heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, R4is selected from halogen, -CN, -OR5, -NR2. -C(O)R, -C(O)NR2, -C(O)OR, or an optionally substituted group selected from C1.6 aliphatic, phenyl, or a 5- to 6- membered hctcroar l having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0099] In some embodiments, R4is hydrogen. In some embodiments, R4is halogen. In some embodiments, R4is fluoro. In some embodiments, R4is chloro. In some embodiments, R4is bromo. In some embodiments. R4is -CN.

[0100] In some embodiments, R4is -OR5. In some embodiments, R4is -OH. In some embodiments, R4is -OCH3. In some embodiments, R4is -OCH2CH3. In some embodiments, R4is -OCF3.

[0101] In some embodiments, R4is -NR2. In some embodiments, R4is -NH2. In some embodiments, R4is -NR2, wherein each R is independently C1-6 aliphatic.

[0102] In some embodiments, R4is -C(O)NR2. In some embodiments, R4is -C(O)NH2. In some embodiments, R4is -C(O)NR2, wherein each R is independently Ci-e aliphatic.

[0103] In some embodiments, R4is -C(O)OR. In some embodiments, R4is -C(O)OH. In some embodiments, R4is -C(O)OR, wherein R is C1-6 aliphatic.

[0104] In some embodiments, R4is -NRC(O)R. In some embodiments. R4is -NHC(O)R. In some embodiments, R4is -NHC(O)R, wherein R is C1-6 aliphatic.

[0105] In some embodiments, R4is -OC(O)R. In some embodiments, R4is -OC(O)R, wherein R is Ci -e aliphatic.

[0106] In some embodiments, R4is optionally substituted Ci-6 aliphatic. In some embodiments, R4is Ci-e aliphatic. In some embodiments, R4is methyl. In some embodiments, R4is ethyl. In some embodiments, R4is n-propyl. In some embodiments, R4is isopropyl. In some embodiments, R4is n -butyl. In some embodiments, R4is s -butyl. In some embodiments, R4is t-butyl.

[0107] In some embodiments, R4is Ci-6 aliphatic, optionally substituted with halogen or -OR°,20BUSINESS.33535339.1wherein R° is hydrogen or Ci-s aliphatic. In some embodiments, R4is Ci-6 aliphatic, optionally substituted with halogen. In some embodiments, R4is -CFFF. In some embodiments, R4is -CHF2. In some embodiments, R4is -CF3. In some embodiments, R4is -CH2CF3. In some embodiments, R4is Ci-g aliphatic, optionally substituted with -OR0, wherein R° is hydrogen or Ci.g aliphatic. In some embodiments, R4is - CH2OH.

[0108] In some embodiments, R4is an optionally substituted 3- to 8-membered saturated or partially unsaturated carbocyclyl or heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, R4is an optionally substituted 3- to 8-membered saturated or partially unsaturated carbocyclyl. In some embodiments, R4is an optionally substituted 3- to 6-membered saturated or partially unsaturated carbocyclyl. In some embodiments, R4is an optionally substituted cyclopropyl. In some embodiments, R4is an optionally substituted cyclobutyl. In some embodiments, R4is an optionally substituted cyclopentyl . In some embodiments, R4is an optionally substituted cyclohexyl. In some embodiments, R4is cyclopropyl. In some embodiments, R4is cyclobutyl. In some embodiments, R4is cyclopentyl. In some embodiments, R4is cyclohexyl.

[0109] In some embodiments, R4is an optionally substituted 3- to 8-membered saturated or partially unsaturated heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, R4is an optionally substituted 3- to 6-membered saturated or partially unsaturated heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur

[0110] In some embodiments, R4is an optionally substituted phenyl. In some embodiments, R4is an optionally substituted 5- to 6-membered heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0111] In some embodiments, R4is selected from hydrogen, halogen, -CN, or optionally substituted C1-6 aliphatic.

[0112] In some embodiments, R7is selected from halogen, -CN, -OR5, -NR2, -C(O)R, -C(O)NR2, - C(O)OR, or an optionally substituted group selected from C1-6 aliphatic, a 3- to 8-membered saturated or partially unsaturated carbocyclyl or heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, phenyl, or a 5- to 6-membered heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, R7is selected from hydrogen, halogen, - CN, -OR5, -NR2, -C(O)R, -C(O)NR2, -C(O)OR, or an optionally substituted group selected from Ci-e aliphatic, phenyl, or a 5- to 6-mcmbcrcd hctcroaryl having 1-3 hctcroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, R7is selected from halogen, -CN, -OR5, -NR2, -C(O)R, -C(O)NR2, -C(O)OR, or an optionally substituted group selected from Ci-6 aliphatic, phenyl, or a 5- to 6- membered heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0113] In some embodiments, R7is hydrogen. In some embodiments, R7is halogen. In some21BUSINESS.33535339.1embodiments, R7is fluoro. In some embodiments, R7is chloro. In some embodiments, R7is bromo. In some embodiments, R7is -CN.

[0114] In some embodiments, R7is -OR5. In some embodiments, R7is -OH. In some embodiments, R7is -OCH3. In some embodiments, R7is -OCH2CH3. In some embodiments, R7is -OCF3.

[0115] In some embodiments, R7is -NR2. In some embodiments, R7is -NH2. In some embodiments, R7is -NR2, wherein each R is independently C1.6 aliphatic.

[0116] In some embodiments, R7is -C(O)NR2. In some embodiments, R7is -C(O)NH2. In some embodiments, R7is -C(O)NR2, wherein each R is independently C1-6 aliphatic.

[0117] In some embodiments, R7is -C(O)OR. In some embodiments, R7is -C(O)OH. In some embodiments, R7is -C(O)OR, wherein R is C1-6 aliphatic.

[0118] In some embodiments, R7is -NRC(O)R. In some embodiments, R7is -NHC(O)R. In some embodiments, R7is -NHC(O)R, wherein R is Ci-e aliphatic.

[0119] In some embodiments, R7is -OC(O)R. In some embodiments. R7is -OC(O)R, wherein R is Ci-6 aliphatic.

[0120] In some embodiments, R7is optionally substituted Ci e aliphatic. In some embodiments, R7is C1-6 aliphatic. In some embodiments, R7is methyl. In some embodiments, R7is ethyl. In some embodiments, R7is n-propyl. In some embodiments, R7is isopropyl. In some embodiments, R7is n-butyl. In some embodiments, R7is s-butyl. In some embodiments. R7is t-butyl.

[0121] In some embodiments. R7is Ci-6 aliphatic, optionally substituted with halogen or -OR°, wherein R° is hydrogen or C1.6 aliphatic. In some embodiments, R7is Ci.g aliphatic, optionally substituted with halogen. In some embodiments, R7is -CH2F. In some embodiments, R7is -CHF2. In some embodiments, R7is -CF3. In some embodiments, R7is -CH2CF3. In some embodiments, R7is Ci-s aliphatic, optionally substituted with -OR°, wherein R° is hydrogen or Ci-6 aliphatic. In some embodiments, R7is - CH2OH.

[0122] In some embodiments, R7is an optionally substituted 3- to 8-membered saturated or partially unsaturated carbocyclyl or heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, R7is an optionally substituted 3- to 8-membered saturated or partially unsaturated carbocyclyl. In some embodiments, R7is an optionally substituted 3- to 6-membered saturated or partially unsaturated carbocyclyl. In some embodiments, R7is an optionally substituted cyclopropyl. In some embodiments, R7is an optionally substituted cyclobutyl. In some embodiments, R7is an optionally substituted cyclopentyl. In some embodiments, R7is an optionally substituted cyclohexyl. In some embodiments, R7is cyclopropyl. In some embodiments, R7is cyclobutyl. In some embodiments, R7is cyclopentyl. In some embodiments, R7is cyclohexyl.22BUSINESS.33535339.1

[0123] In some embodiments, R7is an optionally substituted 3- to 8-membered saturated or partially unsaturated heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, R7is an optionally substituted 3- to 6-mcmbcrcd saturated or partially unsaturated heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur

[0124] In some embodiments, R7is an optionally substituted phenyl. In some embodiments. R7is an optionally substituted 5- to 6-membered heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0125] In some embodiments, R7is selected from hydrogen, halogen, -CN, or optionally substituted Ci-6 aliphatic.

[0126] As defined above and described herein, R5is hydrogen or an optionally substituted group selected from Ci-6 aliphatic or 3-to 8-membered saturated or partially unsaturated carbocyclyl or heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0127] In some embodiments, R5is hydrogen or an optionally substituted Ci-6 aliphatic. In some embodiments, R5is hydrogen. In some embodiments, R5is optionally substituted Ci-6 aliphatic. In some embodiments. R5is Ci-6 aliphatic. In some embodiments, R’ is methyl. In some embodiments, R’ is ethyl. In some embodiments, R5is n-propyl. In some embodiments, R5is isopropyl. In some embodiments, R5is n-butyl. In some embodiments, R5is s-butyl. In some embodiments, R’ is t-butyl.

[0128] In some embodiments, R" is Ci-6 aliphatic, optionally substituted with one or more halogen (e.g., fluoro). In some embodiments, R5is -CFs.

[0129] In some embodiments, R5is an optionally substituted 3-to 8-membered saturated or partially unsaturated carbocyclyl or heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, R5is an optionally substituted 3-to 8-membered saturated or partially unsaturated carbocyclyl. In some embodiments, R5is an optionally substituted 3-to 6-membered saturated or partially unsaturated carbocyclyl. In some embodiments, R5is an optionally substituted cyclopropyl. In some embodiments, R5is an optionally substituted cyclobutyl. In some embodiments, R’ is an optionally substituted cyclopentyl . In some embodiments, R’ is an optionally substituted cyclohexyl. In some embodiments, R5is cyclopropyl. In some embodiments, R5is cyclobutyl. In some embodiments, R5is cyclopentyl. In some embodiments, R5is cyclohexyl.

[0130] In some embodiments, R5is an optionally substituted 3-to 8-membered saturated or partially unsaturated carbocyclyl or heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, R5is an optionally substituted 3- to 6-membered saturated or partially unsaturated heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0131] As defined above and described herein, each Rlaand R9ais independently hydrogen or23BUSINESS.33535339.1optionally substituted Ci.6 aliphatic.

[0132] In some embodiments, Rlais hydrogen. In some embodiments, Rlais optionally substituted Ci-6 aliphatic. In some embodiments, Rlais Ci-e aliphatic. In some embodiments, Rlais methyl. In some embodiments, Rlais ethyl. In some embodiments, Rlais n-propyl. In some embodiments, Rlais isopropyl. In some embodiments, Rlais n-butyl. In some embodiments, Rlais s-butyl. In some embodiments, Rlais t-butyl. In some embodiments, Rlais hydrogen or methyl.

[0133] In some embodiments, R9ais hydrogen. In some embodiments, R9ais optionally substituted Ci-e aliphatic. In some embodiments, R9ais Ci-e aliphatic. In some embodiments, R9ais methyl. In some embodiments, R9ais ethyl. In some embodiments, R9ais n-propyl. In some embodiments, R9ais isopropyl. In some embodiments, R9ais n-butyl. In some embodiments, R9ais s-butyl. In some embodiments, R9ais t-butyl. In some embodiments, R9ais hydrogen or methyl.

[0134] As defined above and described herein, R10issome embodiments, R10is. In some embodiments, R10isembodiments,

[0135] As defined above and described herein, Ring A is a saturated or partially unsaturated 4- to 6- membered monocyclic carbocyclyl, a saturated or partially unsaturated 7- to 8-membered bicyclic spirocyclic carbocyclyl, or a saturated or partially unsaturated 4- to 9-membered fused or bridged bicyclic carbocyclyl.

[0136] In some embodiments. Ring A is a saturated or partially unsaturated 4- to 6-membered monocyclic carbocyclyl. In some embodiments, Ring A is a saturated or partially unsaturated 5-membered monocyclic carbocyclyl. In some embodiments, Ring A is cyclobutyl. In some embodiments, Ring A is cyclobutenyl. In some embodiments. Ringsome embodiments.24BUSINESS.33535339.1Ringsome embodiments, Ring A is cyclopentyl. In some embodiments, Ring A issome embodiments, Ring A issome embodiments, Ring A isIn some embodiments, Ringsome embodiments, Ring A isIn some embodiments, Ring A is cyclopentenyl. hi some embodiments, Ring A is cyclohexyl. In some embodiments, Ring A is cyclohexenyl. In some embodiments. Ring A is(R8)nIn some embodiments, Ring A isIn some embodiments, Ring25BUSINESS.33535339.1(R8)n (R8)„ "N(R6)2A is. In some embodiments, Ring A is. In some embodiments,Ring A isIn some embodiments, Ring A isIn some embodiments. Ring

[0137] In some embodiments. Ring A is a saturated or partially unsaturated 7- to 8-membered bicyclic spirocyclic carbocyclyl. In some embodiments, Ring A is a saturated 7- to 8-membered bicyclic spirocyclic carbocyclyl. In some embodiments, Ring A is a saturated 7-membered bicyclic spirocyclic carbocyclyl. In some embodiments, Ring A is spiro[3.3]heptanyl. In some embodiments, Ring A is, In some embodiments, RingIn some embodiments, Ring A is a partially unsaturated 7-membered bicyclic spirocyclic carbocyclyl. In some embodiments, Ring A is a saturated 8- membered bicyclic spirocyclic carbocyclyl. In some embodiments, Ring A is partially unsaturated 8- membered bicyclic spirocyclic carbocyclyl.

[0138] It will be understood that,26BUSINESS.33535339.1

[0139] In some embodiments, Ring A is a saturated or partially unsaturated 4- to 9-membered fused or bridged bicyclic carbocyclyl. In some embodiments, Ring A is a saturated or partially unsaturated 4- membered fused or bridged bicyclic carbocyclyl. In some embodiments. Ring A is a saturated or partially unsaturated 4-membered bridged bicyclic carbocyclyl. In some embodiments. Ring A is a saturated or partially unsaturated 4-membered fused bicyclic carbocyclyl.

[0140] In some embodiments, Ring A is a saturated or partially unsaturated 5-membered fused or bridged bicyclic carbocyclyl. In some embodiments, Ring A is a saturated or partially unsaturated 5- membered bridged bicyclic carbocyclyl. In some embodiments, Ring A is a saturated or partially unsaturated 5 -membered fused bicyclic carbocyclyl.

[0141] In some embodiments. Ringsome embodiments, Ring.

[0142] In some embodiments. Ring

[0143] In some embodiments, Ring A is a saturated or partially unsaturated 6- to 9-membered fused or bridged bicyclic carbocyclyl.

[0144] In some embodiments, Ring A is a saturated or partially unsaturated 6-membered fused or bridged bicyclic carbocyclyl. In some embodiments. Ring A is a saturated or partially unsaturated 6- membered bridged bicyclic carbocyclyl. In some embodiments, Ring A is a saturated or partially unsaturated 6-membered fused bicyclic carbocyclyl. In some embodiments, Ring A is bicyclohexanyl. In some embodiments. RingIn some embodiments. Ringsome27BUSINESS.33535339.1embodiments, Ringsome embodiments, Ringembodiments, Ringsome embodiments, Ringembodiments. Ring

[0145] In some embodiments, Ring A is a saturated or partially unsaturated 7-membered fused or bridged bicyclic carbocyclyl. In some embodiments, Ring A is a saturated or partially unsaturated 7- membered bridged bicyclic carbocyclyl. In some embodiments, Ring A is a saturated or partially unsaturated 7-membered fused bicyclic carbocyclyl. In some embodiments. Ring A is bicycloheptanyl. In some embodiments. Ringsome embodiments, Ringsome embodiments, Ringsome embodiments, Ring28BUSINESS.33535339.1some embodiments, Ring[nsome embodiments, Ring[nsome embodiments, Ring

[0146] In some embodiments, Ring A is a saturated or partially unsaturated 8-membered fused or bridged bicyclic carbocyclyl. In some embodiments, Ring A is a saturated or partially unsaturated 8- membered bridged bicyclic carbocyclyl. In some embodiments. Ring A is a saturated or partially unsaturated 8-membered fused bicyclic carbocyclyl. In some embodiments. Ringsome embodiments, Ring,

[0147] In some embodiments, Ring A is a saturated or partially unsaturated 9-membered fused or29BUSINESS.33535339.1bridged bicyclic carbocyclyl. In some embodiments, Ring A is a saturated or partially unsaturated 9- membered bridged bicyclic carbocyclyl. In some embodiments, Ring A is a saturated or partially unsaturated 9-membered fused bicyclic carbocyclyl.

[0148] As defined above and described herein, L1is a covalent bond or an optionally substituted bivalent C1-3 saturated or unsaturated, straight or branched, hydrocarbon chain. In some embodiments, L1is a covalent bond. In some embodiments, L1is an optionally substituted bivalent C1.3 saturated or unsaturated, straight or branched, hydrocarbon chain. In some embodiments, L1is a bivalent C1.3 saturated straight hydrocarbon chain. In some embodiments, L1is -CH2-. In some embodiments, L1is a covalent bond or -CH2-.

[0149] As defined above and described herein. Ring B is a saturated or partially unsaturated 4- to 6- membered monocyclic heterocyclyl having one or two nitrogen heteroatoms, a saturated or partially unsaturated 7- to 8-membered bicyclic spirocyclic heterocyclyl having one or two nitrogen heteroatoms, or a saturated or partially unsaturated 4- to 9-membered fused or bridged bicyclic heterocyclyl having one or two nitrogen heteroatoms.

[0150] In some embodiments, Ring B is a saturated or partially unsaturated 7- to 8-membered bicyclic spirocyclic heterocyclyl having one or two nitrogen heteroatoms, or a saturated or partially unsaturated 4- to 9-membered fused or bridged bicyclic heterocyclyl having one or two nitrogen heteroatoms.

[0151] In some embodiments, Ring B is a saturated or partially unsaturated 4- to 6-membered monocyclic heterocyclyl having one or two nitrogen heteroatoms. In some embodiments, Ring B is a saturated or partially unsaturated 6-membered monocyclic heterocyclyl having one nitrogen heteroatom. In some embodiments. Ring B is a saturated or partially unsaturated 6-membered monocyclic heterocyclyl having two nitrogen heteroatoms. In some embodiments. Ring B is piperazinyl. In some embodiments.Ring B is piperidinyl. In some embodiments, Ring B is selected from30BUSINESS.33535339.1embodiments, RingIn some embodiments, Ring B isIn some embodiments, Ring B is

[0152] In some embodiments. Ring B is a saturated or partially unsaturated 7- to 8-membered bicyclic spirocyclic heterocyclyl having one or two nitrogen heteroatoms. In some embodiments, Ring B is a saturated or partially unsaturated 7- to 8-membered bicyclic spirocyclic heterocyclyl having two nitrogen heteroatoms. In some embodiments. Ring B is a saturated or partially unsaturated 7- to 8-membered bicyclic spirocyclic heterocyclyl having a single nitrogen heteroatom. In some embodiments, Ring B is a saturated or partially unsaturated 7-membered bicyclic spirocyclic heterocyclyl having a single nitrogen heteroatom. In some embodiments. Ring B is a saturated or partially unsaturated 8-membered bicyclic spirocyclic heterocyclyl having a single nitrogen heteroatom. In some embodiments, Ring B is 2- azaspiro[3.4]octanyl. In some embodiments, Ring B is 2 -azaspiro [3.4] oct-6 -enyl. In some embodiments,some embodiments,

[0153] In some embodiments, Ring B is a saturated or partially unsaturated 4- to 9-membered fused or bridged bicyclic heterocyclyl having one or two nitrogen heteroatoms.31BUSINESS.33535339.1

[0154] In some embodiments, Ring B is a saturated or partially unsaturated 4- to 9-membered fused or bridged bicyclic heterocyclyl having a single nitrogen heteroatom. In some embodiments, Ring B is a saturated or partially unsaturated 5 -membered fused or bridged bicyclic heterocyclyl having a single nitrogen heteroatom. In some embodiments, Ring B is a saturated or partially unsaturated 5-membered bridged bicyclic heterocyclyl having a single nitrogen heteroatom. In some embodiments, Ring B is a saturated or partially unsaturated 5-membered fused bicyclic heterocyclyl having a single nitrogen heteroatom.

[0155] In some embodiments, Ring B is a saturated or partially unsaturated 6-membered fused or bridged bicyclic heterocyclyl having a single nitrogen heteroatom. In some embodiments, Ring B is a saturated or partially unsaturated 6-membered bridged bicyclic heterocyclyl having a single nitrogen heteroatom. In some embodiments, Ring B is a saturated or partially unsaturated 6-membered fused bicyclic heterocyclyl having a single nitrogen heteroatom.

[0156] In some embodiments, Ring B is 3-azabicyclo[3.1.0]hexanyl. In some embodiments, Ring B is

[0157] In some embodiments, Ring B is a saturated or partially unsaturated 8- to 9-membered fused or bridged bicyclic heterocyclyl having a single nitrogen heteroatom. In some embodiments, Ring B is a saturated or partially unsaturated 9-membered fused or bridged bicyclic heterocyclyl having a single nitrogen heteroatom. In some embodiments. Ring B is 2,3,3a,6,7,7a-hexahydro-lH-indolyl. In some embodiments, RingIn some embodiments, Ring. In some32BUSINESS.33535339.1

[0158] In some embodiments, Ring B is a saturated or partially unsaturated 4- to 9-membered fused or bridged bicyclic heterocyclyl having two nitrogen heteroatoms. In some embodiments, Ring B is a saturated or partially unsaturated 7- to 9-membered fused or bridged bicyclic heterocyclyl having two nitrogen heteroatoms. In some embodiments, Ring33BUSINESS.33535339.1some embodiments.In some embodiments, n some embodiments,In some embodiments,some embodiments,

[0162] As defined above and described herein, each R6is independently hydrogen or optionally substituted Ci-6 aliphatic; and each R8is independently hydrogen, halogen, -CN, -OR, -NR2, or optionally substituted Cve aliphatic; or an R6and an R8group may be taken together to form an optionally substituted 3- to 8-membered saturated or partially unsaturated bridged or fused carbocyclyl or heterocyclyl having 1- 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or; two R8groups on the same atom may be taken together to form an optionally substituted 3- to 8-membered saturated or partially unsaturated spirocarbocyclyl or spiroheterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or two R8groups on different atoms may be taken together to fonn an optionally substituted 3- to 8-membered saturated or partially unsaturated bridged or fused carbocyclyl or heterocyclyl34BUSINESS.33535339 1having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0163] In some embodiments, each R6and R8is independently hydrogen or optionally substituted Ci- e aliphatic; or an R6and an R8group may be taken together to form an optionally substituted 3- to 8- membered saturated or partially unsaturated bridged or fused carbocyclyl or heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or two R8groups on the same atom may be taken together to fonn an optionally substituted 3- to 8-membered saturated or partially unsaturated spirocarbocyclyl or spiroheterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or two R8groups on different atoms may be taken together to form an optionally substituted 3- to 8-membered saturated or partially unsaturated bridged or fused carbocycly l or heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0164] In some embodiments. R6is hydrogen or optionally substituted Ci-6 aliphatic. In some embodiments, R' is hydrogen. In some embodiments, R6is optionally substituted Ci.e aliphatic. In some embodiments, R6is Ci-e aliphatic. In some embodiments, R6is methyl. In some embodiments, R6is ethyl. In some embodiments, R6is n-propyl. In some embodiments, R6is isopropyl. In some embodiments, Rbis n-butyl. In some embodiments, R6is s-butyl. In some embodiments, R6is t-butyl. In some embodiments, R6is hydrogen or methyl.

[0165] In some embodiments, each R8is independently hydrogen, halogen, -CN, -OR, -NR2, or optionally substituted Ci-e aliphatic. In some embodiments, each R8is independently hydrogen or optionally substituted Ci-e aliphatic. In some embodiments, R8is hydrogen. In some embodiments, R8is halogen. In some embodiments, R8is fluoride. In some embodiments, R8is -CN. In some embodiments, R8is -OR. In some embodiments, R8is -NR2. In some embodiments, R8is optionally substituted Ci.g aliphatic. In some embodiments, R8is C1-6 aliphatic. In some embodiments. R8is methyl. In some embodiments. R8is ethyl. In some embodiments, R8is n-propyl. In some embodiments, R8is isopropyl. In some embodiments, R8is n-butyl. In some embodiments, R8is s-butyl. In some embodiments, R8is t-butyl.

[0166] In some embodiments, an R6and an R8group may be taken together to fonn an optionally substituted 3- to 8-membered saturated or partially unsaturated bridged or fused carbocyclyl or heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, embodiments, an R6and an R8group may be taken together to form an optionally substituted 3- to 8-membered saturated or partially unsaturated bridged or fused carbocyclyl. embodiments, an R6and an R8group may be taken together to form an optionally substituted 3- to 8-membered saturated or partially unsaturated bridged or fused heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0167] In some embodiments, two R8groups on the same atom may be taken together to form an optionally substituted 3- to 8-membered saturated or partially unsaturated spirocarbocyclyl or spiroheterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some35BUSINESS.33535339.1embodiments, two R8groups on the same atom may be taken together to form an optionally substituted 3- to 8-membered saturated or partially unsaturated spirocarbocyclyl. In some embodiments, two R8groups on the same atom may be taken together to form an optionally substituted 3- to 8-membered saturated or partially unsaturated spiroheterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0168] In some embodiments, two R8groups on different atoms may be taken together to form an optionally substituted 3- to 8-membered saturated or partially unsaturated bridged or fused carbocyclyl or heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, two R8groups on different atoms may be taken together to fomr an optionally substituted 3- to 8-membered saturated or partially unsaturated bridged or fused carbocyclyl. In some embodiments, two R8groups on different atoms may be taken together to form an optionally substituted 3- to 8-membered saturated or partially unsaturated bridged or fused heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0169] As defined above and described herein, n is 0, 1, 2, 3, 4, 5, 6, 7, or 8. In some embodiments, n is 0, 1, 2, 3, or 4. In some embodiments, n is 0, 1. or 2. In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, n is 4. In some embodiments, n is 5. In some embodiments, n is 6. In some embodiments, n is 7. In some embodiments, n is 8.

[0170] As defined above and described herein, each R is independently hydrogen or optionally substituted Ci.g aliphatic. In some embodiments, R is hydrogen. In some embodiments, R is optionally substituted Ci-6 aliphatic. In some embodiments, R is Ci-e aliphatic. In some embodiments, R is methyl. In some embodiments, R is ethyl. In some embodiments, R is n-propyl. In some embodiments, R is isopropyl. In some embodiments, R is n-butyl. In some embodiments, R is s-butyl. In some embodiments, R is t-butyl.

[0171] In some embodiments, the present disclosure provides a compound of formula I”-a:or a pharmaceutically acceptable salt thereof, wherein each of Ring A, X1, X2, X3, X4, X7, X9, R6, R8, L1,36BUSINESS.33535339.1and n is defined and described in classes and subclasses herein, both singly and in combination.

[0172] In some embodiments, the present disclosure provides a compound of formula I”-b:or a pharmaceutically acceptable salt thereof, wherein each of Ring B. X1. X2. X3, X4, X7, X8, X9, R6, R8, and n is defined and described in classes and subclasses herein, both singly and in combination.

[0173] In some embodiments, the present disclosure provides a compound of formulae I-a, I-b, I-c, I- d, or I-e:37BUSINESS.33535339.1or a pharmaceutically acceptable salt thereof, wherein each of X1, X2, X3, X4, R6, R7, R8, and n is defined and described in classes and subclasses herein, both singly and in combination.

[0174] It will be understood that, unless otherwise specified or prohibited by the foregoing definition of formulae I-a. I-b. I-c, I-d, or I-e. embodiments of variables X1, X2, X3. X4. R6. R7. R8, and n as defined above and described in classes and subclasses herein, also apply to compounds of formulae I-a, I-b, I-c, I- d, or I-e, both singly and in combination.

[0175] In some embodiments, the present disclosure provides a compound of formulae II, Il-a, Il-b,II-c. Il-d, or Il-e:38BUSINESS.33535339.1or a pharmaceutically acceptable salt thereof, wherein each of R1, R2, R3, R4, R6, R7, R8, and n is defined and described in classes and subclasses herein, both singly and in combination.39BUSINESS.33535339.1

[0176] It will be understood that, unless otherwise specified or prohibited by the foregoing definition of formulae II, Il-a, Il-b, II-c, Il-d, or Il-e, embodiments of variables R1, R2, R3, R4, R6, R7, R8, and n as defined above and described in classes and subclasses herein, also apply to compounds of formulae II, II- a, Il-b, II-c, Il-d, or Il-e, both singly and in combination.

[0177] In some embodiments, the present disclosure provides a compound of formulae III. Ill-a. III- b, III-c, Ill-d, or Ill-e:40BUSINESS.33535339.1or a pharmaceutically acceptable salt thereof, wherein each of R1, R3, R4, R6, R7, R8, and n is defined and described in classes and subclasses herein, both singly and in combination.

[0178] It will be understood that, unless otherwise specified or prohibited by the foregoing definition of formulae III, III-a, III-b, III-c, Ill-d, or Ill-e, embodiments of variables R1, R3, R4, R6, R7, R8, and n as defined above and described in classes and subclasses herein, also apply to compounds of formulae III, III-a, III-b, III-c, Ill-d, or Ill-e, both singly and in combination.

[0179] In some embodiments, the present disclosure provides a compound of formulae IV, IV-a, IV- b. IV-c, IV-d. or lV-e:41BUSINESS.33535339.1BUSINESS.33535339.1or a pharmaceutically acceptable salt thereof, wherein each of R1, R2. R4, R6, R7, R8, and n is defined and described in classes and subclasses herein, both singly and in combination.

[0180] It will be understood that, unless otherwise specified or prohibited by the foregoing definition of formulae IV, IV-a, IV-b, IV-c, IV-d, or IV-e, embodiments of variables R1, R2, R4, R6, R7, R8, and n as defined above and described in classes and subclasses herein, also apply to compounds of formulae IV, IV- a, IV-b, IV-c, IV-d, or IV-e. both singly and in combination.[00181 J In some embodiments, the present disclosure provides a compound of formulae V, V-a, V-b, V-c, V-d, or V-e:43BUSINESS.33535339.1or a pharmaceutically acceptable salt thereof, wherein each of R1, R2, R3, R6, R7, Rs, and n is defined and described in classes and subclasses herein, both singly and in combination.[00182J It will be understood that, unless otherwise specified or prohibited by the foregoing definition44BUSINESS.33535339.1of formulae V, V-a, V-b, V-c, V-d, or V-e, embodiments of variables R1, R2, R3, R6, R7, R8, and n as defined above and described in classes and subclasses herein, also apply to compounds of formulae V, V-a, V-b, V- c, V-d, or V-e, both singly and in combination.

[0183] In some embodiments, the present disclosure provides a compound of fonnulae VI. Vl-a, VI- b, VI-c, Vl-d. or Vi e45BUSINESS.33535339.1or a pharmaceutically acceptable salt thereof, wherein each of R1. R3. R6. R7. R8. and n is defined and described in classes and subclasses herein, both singly and in combination.

[0184] It will be understood that, unless otherwise specified or prohibited by the foregoing definition of formulae VI, Vl-a, Vl-b, VI-c, Vl-d, or Vl-e, embodiments of variables R1, R3, R°, R7, R8, and n as defined above and described in classes and subclasses herein, also apply to compounds of fonnulae VI, VI- a, Vl-b, VI-c, Vl-d. or Vl-e, both singly and in combination.

[0185] In some embodiments, the present disclosure provides a compound of formulae VII, VILa, VH-b, VII-c, VH-d, or Vil e:46BUSINESS.33535339.1BUSINESS.33535339.1or a pharmaceutically acceptable salt thereof, wherein each of R2. R4. R6. R7. R8. and n is defined and described in classes and subclasses herein, both singly and in combination.

[0186] It will be understood that, unless otherwise specified or prohibited by the foregoing definition of fonnulae VII, VH-a, VH-b, VII-c, VH-d, or VH-e, embodiments of variables R2, R4, R6, R7, R8, and n as defined above and described in classes and subclasses herein, also apply to compounds of fonnulae VTI, Vil a. Vll-b, VII-c, VH-d, or VH-e, both singly and in combination.[00187J In some embodiments, the present disclosure provides a compound of formulae VIII, VUI-a, VIILb, VIII-c, VUI-d, or Vlll-e:48BUSINESS.33535339.1or a pharmaceutically acceptable salt thereof, wherein each of R1, R4, R6, R7, R8, and n is defined and described in classes and subclasses herein, both singly and in combination.49BUSINESS.33535339.1

[0188] It will be understood that, unless otherwise specified or prohibited by the foregoing definition of formulae VIII, Vlll-a, Vlll-b, VIII-c, VUI-d, or Vlll-e, embodiments of variables R1, R4, R6, R7, R8, and n as defined above and described in classes and subclasses herein, also apply to compounds of formulae VIII, VUI-a, Vlll-b, VIII-c, VUI-d, or VUI-e. both singly and in combination.

[0189] In some embodiments, the present disclosure provides a compound of formulae IX-a. IX-b, IX-c, IX-d, IX-e, or IX-f:50BUSINESS.33535339.1IX-dor a pharmaceutically acceptable salt thereof, wherein each ofX1, X2, X3, X4, X7, X9, R6, R8, and n is defined and described in classes and subclasses herein, both singly and in combination.

[0190] It will be understood that, unless otherwise specified or prohibited by the foregoing definition of formulae IX-a, IX-b, IX-c, IX-d, IX-e, or IX-f, embodiments of variables X1, X2, X3, X4, X7, X9, R6, R8, and n as defined above and described in classes and subclasses herein, also apply to compounds of formulae IX-a, IX-b, IX-c, IX-d, IX-e, or IX-f, both singly and in combination.

[0191] In some embodiments, the present disclosure provides a compound of fonnula X:or a pharmaceutically acceptable salt thereof, wherein each of R1, X2, X3, X4, R7and R10is defined and described in classes and subclasses herein, both singly and in combination.

[0192] It will be understood that, unless otherwise specified or prohibited by the foregoing definition of formula X, embodiments of variables R1, X2, X3, X4, R7and R10as defined above and described in classes and subclasses herein, also apply to compounds of formula X, both singly and in combination.

[0193] In some embodiments, the present disclosure provides a compound of formulae XI, Xl-a, XI- b, or XI-c:51BUSINESS.33535339.1or a pharmaceutically acceptable salt thereof, wherein each of R1, X2, X3, X4, R10, R6, R8, and n is defined and described in classes and subclasses herein, both singly and in combination.

[0194] It will be understood that, unless otherwise specified or prohibited by the foregoing definition of formulae XI, Xl-a, Xl-b, or XI-c, embodiments of R1, X2, X3, X4, R10, R6, R8, and n as defined above and described in classes and subclasses herein, also apply to compounds of formulae XI, Xl-a, Xl-b, or XI-c, both singly and in combination.

[0195] In some embodiments, the present disclosure provides a compound of fonnulae XII, XH-a, XH-b. or XII-c:52BUSINESS.33535339.1or a pharmaceutically acceptable salt thereof, wherein each of R1, R3, R4, R10, R6, R8, and n is defined and described in classes and subclasses herein, both singly and in combination.

[0196] It will be understood that, unless otherwise specified or prohibited by the foregoing definition of formulae XII, XH-a, Xll-b, or XII-c, embodiments of R1, R3, R4, R10, R6, R8, and n as defined above and described in classes and subclasses herein, also apply to compounds of formulae XII, Xll-a, Xll-b, or XII-c, both singly and in combination.

[0197] In some embodiments, the present disclosure provides a compound of formulae XIII, XHI-a, XHI-b, or XIII-c:53BUSINESS.33535339.1or a pharmaceutically acceptable salt thereof, wherein each of R1, R2, R4, R10, R6, R8, and n is defined and described in classes and subclasses herein, both singly and in combination.

[0198] It will be understood that, unless otherwise specified or prohibited by the foregoing definition of formulae XIII, XHI-a, Xlll-b, or XIII-c, embodiments of R1, R2, R4, R10, R6, R8, and n as defined above and described in classes and subclasses herein, also apply to compounds of formulae XIII, Xlll-a, XHI-b, or XIII-c, both singly and in combination.

[0199] In some embodiments, the present disclosure provides a compound of formulae XIV, XlV-a, XV. or XV-a:54BUSINESS.33535339.1or a pharmaceutically acceptable salt thereof, wherein each of Rla, X2, X3, X4, R2, R3, R4, and R10is defined and described in classes and subclasses herein, both singly and in combination.

[0200] It will be understood that, unless otherwise specified or prohibited by the foregoing definition of formulae XIV, XlV-a, XV, or XV-a, embodiments of Rla, X2, X3, X4, R2, R3, R4, and R10as defined above and described in classes and subclasses herein, also apply to compounds of formulae XIV, XlV-a, XV, or XV-a, both singly and in combination.

[0201] In some embodiments, the present disclosure provides a compound selected from those depicted in Table 1, or a pharmaceutically acceptable salt thereof.Table 155BUSINESS.33535339.156BUSINESS.33535339.157BUSINESS.33535339.158BUSINESS.33535339.159BUSINESS.33535339.160BUSINESS.33535339.161BUSINESS.33535339.162BUSINESS.33535339.1410095-003WQ (221371)63BUSINESS.33535339.1

[0202] In some embodiments, the present invention provides a compound set forth in Table 1, above, or a pharmaceutically acceptable salt thereof. In some embodiments, the present invention provides a compound set forth in Table 1, above.4. Uses, Formulation and AdministrationPharmaceutically acceptable compositions

[0203] According to another embodiment, the invention provides a composition comprising a provided compound, or a pharmacally acceptable salt thereof, and a pharmaceutically acceptable carrier, adjuvant, or vehicle. In some embodiments, the amount of compound in compositions of this invention is such that is effective to measurably activate 5-HT2AR, or a mutant thereof, in a biological sample or in a patient. In some embodiments, a composition of this invention is formulated for administration to a patient in need of such composition.

[0204] In some embodiments, the present invention provides a pharmaceutical composition comprising a provided compound (described in embodiments herein, both singly and in combination), or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier, adjuvant, or64BUSINESS.33535339.1vehicle. For example, in some embodiments, the present invention provides a pharmaceutical composition comprising a provided compound, or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier, adjuvant, or vehicle. In some embodiments, the present invention provides a pharmaceutical composition comprising a compound set forth in Table 1 above, or a pharmacally acceptable salt thereof, together with a pharmacally acceptable carrier, adjuvant, or vehicle.

[0205] The term ‘'patient” as used herein, means an animal, preferably a mammal, and most preferably a human.

[0206] The term “pharmacally acceptable carrier, adjuvant, or vehicle” refers to a non-toxic carrier, adjuvant, or vehicle that does not destroy the pharmacological activity of the compound with which it is fonnulated. Pharmaceutically acceptable carriers, adjuvants or vehicles that may be used in the compositions of this invention include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, semm proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene- polyoxypropylene-block polymers, polyethylene glycol and wool fat.

[0207] Compositions of the present invention may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally. vaginally or via an implanted reservoir. The term "parenteral" as used herein includes subcutaneous, intravenous, intramuscular, intra-articular. intra-synovial, intrastemal. intrathecal, intrahepatic. intralesional and intracranial injection or infusion techniques. Preferably, the compositions are administered orally, intraperitoneally or intravenously. Sterile injectable forms of the compositions of this invention may be aqueous or oleaginous suspension. These suspensions may be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium.

[0208] For this purpose, any bland fixed oil may be employed including synthetic mono- or diglycerides. Fatty acids are useful in the preparation of injectables, as are natural pharmaceutically- acceptable oils. These oil solutions or suspensions may also contain a long-chain alcohol diluent or dispersant, for the formulation of pharmaceutically acceptable dosage forms including emulsions and suspensions. Other commonly used surfactants and other emulsifying agents or bioavailability enhancers which are commonly used in the manufacture of pharmaceutically acceptable solid, liquid, or other dosage65BUSINESS.33535339.1forms may also be used for the purposes of formulation.

[0209] Pharmaceutically acceptable compositions of this invention may be orally administered in any orally acceptable dosage fonn including, but not limited to, capsules, tablets, aqueous suspensions or solutions. In the case of tablets for oral use, carriers may be included. Lubricating agents are also typically added. For oral administration in a capsule fonn, diluents may be included. When aqueous suspensions are required for oral use, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening, flavoring or coloring agents may also be added. Such formulations may be administered with or without food. In some embodiments, pharmaceutically acceptable compositions of this invention are administered without food. In other embodiments, pharmaceutically acceptable compositions of this invention are administered with food.

[0210] Alternatively, pharmaceutically acceptable compositions of this invention may be administered in the form of suppositories for rectal administration. These can be prepared by mixing the agent with a suitable non-irritating excipient that is solid at room temperature but liquid at rectal temperature and therefore will melt in the rectum to release the drug.

[0211] Pharmaceutically acceptable compositions of this invention may also be administered topically, especially when the target of treatment includes areas or organs readily accessible by topical application, including diseases of the eye, the skin, or the lower intestinal tract. Suitable topical formulations are readily prepared for each of these areas or organs.

[0212] Topical application for the lower intestinal tract can be effected in a rectal suppository’ formulation (see above) or in a suitable enema formulation. Topically-transdermal patches may also be used.

[0213] For topical applications, provided pharmaceutically acceptable compositions may be formulated in a suitable ointment containing the active component suspended or dissolved in one or more carriers. Alternatively, provided pharmaceutically acceptable compositions can be formulated in a suitable lotion or cream containing the active components suspended or dissolved in one or more pharmaceutically acceptable carriers

[0214] For ophthalmic use, provided pharmaceutically acceptable compositions may be formulated as micronized suspensions in isotonic, pH adjusted sterile saline, or, preferably, as solutions in isotonic, pH adjusted sterile saline, either with or without a preservative. Alternatively, for ophthalmic uses, the pharmacally acceptable compositions may be formulated in an ointment.

[0215] Pharmaceutically acceptable compositions of this invention may also be administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques well-known in the art of pharmaceutical formulation and may be prepared as solutions in saline, employing suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and / or other conventional solubilizing or 66BUSINESS.33535339.1dispersing agents.

[0216] Tire amount of compounds of the present invention that may be combined with the carrier materials to produce a composition in a single dosage form will vary depending upon the host treated, the particular mode of administration.

[0217] It should also be understood that a specific dosage and treatment regimen for any particular patient will depend upon a variety of factors, including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, rate of excretion, drug combination, and the judgment of the treating physician and the severity of the particular disease being treated. The amount of a compound of the present invention in the composition will also depend upon the particular compound in the composition.Uses of Compounds and Pharmaceutically Acceptable Compositions

[0218] In some embodiments, provided compounds and compositions are for use in medicine.

[0219] Compounds and compositions described herein are generally useful as agonists of 5-HT2AR.

[0220] According to one embodiment, the invention relates to a method of activating 5-HT2AR. or a mutant thereof, in a biological sample comprising contacting said biological sample with a provided compound, or a pharmaceutically acceptable salt thereof, or a composition comprising said compound.

[0221] The term “biological sample’’, as used herein, includes, without limitation, cell cultures or extracts thereof: biopsied material obtained from a mammal or extracts thereof; and blood, saliva, urine, feces, semen, tears, or other body fluids or extracts thereof. In some embodiments, 5-HT2AR is from a biological sample. In some embodiments, the biological sample is taken from a subject.

[0222] Activation of 5-HT2AR, or a mutant thereof, in a biological sample is useful for a variety of purposes that are known to one of skill in the art. Examples of such purposes include, but are not limited to. blood transfusion, organ-transplantation, biological specimen storage, and biological assays.

[0223] In some embodiments, the invention also provides a compound described herein, or a pharmaceutically acceptable salt thereof, or pharmaceutical compositions described herein, for use in a method for activating 5-HT2AR, or a mutant thereof, as described herein.

[0224] In some embodiments, the invention also provides a compound described herein, or a pharmacally acceptable salt thereof, or pharmacal compositions described herein, for use in a method for selectively activating 5-HT2AR, or a mutant thereof, (e.g.. over the 5-HT2B and / or 5-HT2C receptors, or mutants thereof) as described herein. In some embodiments, such methods include administering to a patient a provided compound, or a pharmaceutically acceptable salt thereof, wherein the compound selectively binds to 5-HT2AR over 5-HT2BR and / or 5-HT2CR. The method of selectively agonizing 5-HT2AR, or a mutant thereof, can be used to treat, ameliorate, and / or prevent disorders that are 67BUSINESS.33535339.1affected by, associated with, or would benefit from selective activation of 5-HT2AR. In selectively binding to and activating 5-HT2AR, or a mutant thereof, over the 5-HT2BR and / or 5-HT2CR, or one or more mutants thereof, the method provides, for example, reduced side effects such as, but not limited to, drug- induced valvular heart disease associated with binding and activating 5-HT2BR. In some embodiments, a provided compound is a 5-HT2BR, or a mutant thereof, antagonist. In some embodiments, a provided compound is a 5-HT2CR, or a mutant thereof, antagonist.

[0225] In some embodiments, the invention also provides a compound described herein, or a pharmaceutically acceptable salt thereof, or pharmaceutical compositions described herein, for use in a method for treating a 5-HT2AR-mediated disorder as described herein. Such disorders are described in detail herein.

[0226] G protein-coupled receptors (GPCRs) signal through numerous pathways, including disease- associated but also non-disease-associated pathways, and as a result modulation of GPCRs can cause undesired side effects. Modulators of GPCRs can bind and preferentially activate specific pathways over others, often referred to as ligand-mediated bias or pathway bias. 5-HT2AR may interact with multiple signaling pathways upon ligand binding, e.g., pathways that engage with G proteins or p-arrestins. See Kossatz. E.. et al. Nature Communications 2024, 15:4307. In some embodiments, the invention also provides a compound described herein, or a pharmaceutically acceptable salt thereof, or pharmaceutical compositions described herein, for use in a method for binding 5-HT2AR, or a mutant thereof, resulting in increased (“biased”) activation of a particular signaling pathway (e.g., a G protein signaling pathway) over others (e.g., a -arrcstin signaling pathway). In some embodiments, provided methods include administering to a patient a provided compound, or a pharmaceutically acceptable salt thereof, wherein the compound binds to 5-HT2AR and results in increased (“biased”) activation of a G protein signaling pathway over a P-arrestin signaling pathway. In some embodiments, provided methods include administering to a patient a provided compound, or a pharmaceutically acceptable salt thereof, wherein the compound is characterized in that, upon binding 5-HT2AR, or a mutant thereof, the compound effects increased (“biased”) activation of a G protein signaling pathway over a p-arrcstin signaling pathway.

[0227] In some embodiments, provided methods include increasing activation of a G protein signaling pathway associated with 5-HT2AR over a P-arrestin signaling pathway associated with 5-HT2AR in a patient in need thereof, comprising administering to the patient a provided compound, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable composition thereof.

[0228] In some embodiments, G protein signaling pathways are evaluated through detection of calcium, e.g., as described in Example 2. In some embodiments, p-arrestin signaling pathways are evaluated as described in Example 3.

[0229] In some embodiments, G protein signaling pathway is increased by at least 50%, at least 100%,68BUSINESS.33535339.1410095-003WQ (221371) at least 500%, at least 1,000%, at least 5,000%, or at least 10,000% (e.g., as measured in Example 2) as compared to [3-arrestin signaling pathways (e.g., as measured in Example 3).

[0230] In some embodiments, a compound described herein, or a pharmaceutically acceptable salt thereof, or pharmaceutical compositions described herein, may exhibit anxiolytic, anti-depressive, and antidrug abuse actions, without exhibiting substantial psychedelic actions, for example, hallucinogenic actions. For example, a provided compound, or a pharmaceutically acceptable salt thereof, may confer antidepressant like activities without incurring psychedelic drug-like actions. For example, in some embodiments, a provided compound, or a pharmaceutically acceptable salt thereof, may be safe and effective for use in a method described herein, yet lack the hallucinogenic effects of known psychedelics such as, for example, DMT and psilocybin. In some embodiments, a patient does not experience a hallucinogenic effect as a result of the activating or treating.

[0231] The activity of a compound, or a pharmaceutically acceptable salt thereof, utilized in this invention as an activator of 5-HT2AR, or a mutant thereof, may be assayed in vitro, in vivo or in a cell line. In vitro assays include assays that determine activation and / or the subsequent functional consequences of activated 5-HT2AR. or a mutant thereof. Alternate in vitro assays quantitate the ability of the agonist to bind to 5-HT2AR. or a mutant thereof. Agonist binding may be measured by radiolabeling the compound prior to binding, isolating the compound / 5-HT2AR complex and determining the amount of radiolabel bound. Alternatively, agonist binding may be determined by running a competition experiment where additional agonists are incubated with 5-HT2AR, or a mutant thereof, bound to known radioligands. Detailed conditions for assaying a compound utilized in this invention as an agonist of 5-HT2AR, or a mutant thereof, are set forth in the Examples below.

[0232] As used herein, the terms “treatment,” “treat,” and “treating” refer to reversing, alleviating, delaying the onset of, or inhibiting the progress of a disease or disorder, or one or more symptoms thereof, as described herein. In some embodiments, treatment may be administered after one or more symptoms have developed. In other embodiments, treatment may be administered in the absence of symptoms. For example, treatment may be administered to a susceptible individual prior to the onset of symptoms (e.g., in light of a history of symptoms and / or in light of genetic or other susceptibility factors). Treatment may also be continued after symptoms have resolved, for example to prevent or delay their recurrence.

[0233] Provided compounds are agonists of 5-HT2AR, or a mutant thereof, and are therefore useful for treating one or more disorders associated with activity of 5-HT2AR. In some embodiments, the present invention provides a method for treating a 5-HT2AR-mediated disorder comprising administering to a patient in need thereof provided compound, or a pharmaceutically acceptable salt thereof, or pharmaceutically acceptable composition thereof.

[0234] As used herein, the term “5-HT2AR-mediated” disorders, diseases, and / or conditions as used69BUSINESS.33535339.1herein means any disease or other deleterious condition in which 5-HT2AR, or a mutant thereof, are known to play a role. Accordingly, another embodiment of the present invention relates to treating or lessening the severity of one or more diseases in which 5-HT2AR, or a mutant thereof, are known to play a role.

[0235] In some embodiments, the present invention provides a method for treating a neurological disease, disorder, or condition comprising administering to a patient in need thereof provided compound, or a pharmaceutically acceptable salt thereof, or pharmaceutically acceptable composition thereof.

[0236] Non-limiting examples of a neurological disease or disorder include depression, anxiety, substance abuse, and headaches. Headaches that can be treated with the methods herein include, but are not limited to, migraine headaches and cluster headaches.

[0237] In some embodiments, the present invention provides a method for treating a depressive disease, disorder, or condition comprising administering to a patient in need thereof provided compound, or a pharmaceutically acceptable salt thereof, or pharmaceutically acceptable composition thereof. In some embodiments, the depressive disorder is a major depressive disorder. In other embodiments, the depressive disorder includes treatment resistant depressions.

[0238] In some embodiments, tire present invention provides a method for treating an anxiety disease, disorder, or condition comprising administering to a patient in need thereof provided compound, or a pharmaceutically acceptable salt thereof, or pharmaceutically acceptable composition thereof. In some embodiments, the anxiety disorder is generalized anxiety disorder. In other embodiments, the anxiety disorder is social anxiety disorder.

[0239] In some embodiments, the present invention provides a method for treating trauma and / or stress disease, disorder, or condition comprising administering to a patient in need thereof provided compound, or a pharmaceutically acceptable salt thereof, or pharmaceutically acceptable composition thereof. In some embodiments, such a disorder is post-traumatic stress disorder. In other embodiments, such a disorder is an adjustment disorder.

[0240] In some embodiments, the present invention provides a method for treating an obsessive- compulsive disorder, e.g., body dysmorphic disorder, comprising administering to a patient in need thereof provided compound, or a pharmaceutically acceptable salt thereof, or pharmaceutically acceptable composition thereof.

[0241] In some embodiments, the present invention provides a method for treating an eating disorder comprising administering to a patient in need thereof provided compound, or a pharmaceutically acceptable salt thereof, or pharmaceutically acceptable composition thereof, hr some embodiments, the eating disorder is anorexia. In other embodiments, the eating disorder is bulimia.

[0242] In some embodiments, the present invention provides a method for treating a sleep-wake disorder, e.g., insomnia, comprising administering to a patient in need thereof provided compound, or a 70BUSINESS.33535339.1pharmaceutically acceptable salt thereof, or pharmaceutically acceptable composition thereof.

[0243] In some embodiments, the present invention provides a method for treating a psychotic disorder comprising administering to a patient in need thereof provided compound, or a pharmaceutically acceptable salt thereof, or pharmacally acceptable composition thereof. In some embodiments, the psychotic disorder is schizophrenia. In other embodiments, the psychotic disorder is schizoaffective disorder. In still other embodiments, the psychotic disorder is schizotypal personality disorder.

[0244] In some embodiments, the present invention provides a method for treating a substance-related and / or addictive disease, disorder, or condition comprising administering to a patient in need thereof provided compound, or a pharmaceutically acceptable salt thereof, or pharmacally acceptable composition thereof. In some embodiments, such a disorder is an alcohol use disorder. In other embodiments, such a disorder is an opioid use disorder. In still other embodiments, such a disorder is a tobacco use disorder. For example, in some embodiments provided compound, or a pharmaceutically acceptable salt thereof, may be useful in facilitating smoking cessation.

[0245] In some embodiments, the present invention provides a method for treating a neurocognitive disease, disorder, or condition comprising administering to a patient in need thereof provided compound, or a pharmaceutically acceptable salt thereof, or pharmaceutically acceptable composition thereof. In some embodiments, the neurocognitive disorder includes those due to a primary neurodegenerative disease, for example, Alzheimer's disease or Parkinson’s disease.

[0246] In some embodiments, the present invention provides a method for treating a personality disorder comprising administering to a patient in need thereof provided compound, or a pharmacally acceptable salt thereof, or pharmaceutically acceptable composition thereof.

[0247] In some embodiments, the present invention provides a method for treating an autism spectrum disorder comprising administering to a patient in need thereof provided compound, or a pharmaceutically acceptable salt thereof, or pharmaceutically acceptable composition thereof.

[0248] In some embodiments, the present invention provides a method for treating a bipolar disorder comprising administering to a patient in need thereof provided compound, or a pharmaceutically acceptable salt thereof, or pharmaceutically acceptable composition thereof. In some embodiments, the bipolar disorder is bipolar I disorder. In some embodiments, the bipolar disorder is bipolar II disorder.

[0249] In some embodiments, the present invention provides a method for treating a pain disease, disorder, or condition comprising administering to a patient in need thereof provided compound, or a pharmaceutically acceptable salt thereof, or pharmaceutically acceptable composition thereof. In some embodiments, the pain disorder is neuropathic pain. In some embodiments, the pain disorder is migraine. In some embodiments, the pain disorder is a cluster headache. In some embodiments, the pain disorder is a trigeminal neuralgia. In some embodiments, the pain disorder is cancer pain. In some embodiments, the 71BUSINESS.33535339.1pain disorder is a regional pain disorder. In some embodiments, the pain disorder is phantom limb pain. In some embodiments, a contemplated pain disorder is a chronic pain.EXAMPLES

[0250] As depicted in the Examples below, in certain exemplary embodiments, compounds are prepared according to the following general procedures. It will be appreciated that, although the general methods depict the synthesis of certain compounds of the present disclosure, the following general methods. and other methods known to one of ordinary skill in the art, can be applied to all compounds and subclasses and species of each of these compounds, as described herein.

[0251] General Scheme 172BUSINESS.33535339.1Eluting fraction 1 + From Eluting fraction 2 Eluting fraction 1 + Eluting fraction 2

[0252] General Scheme 2Eluting fraction 1 + Eluting fraction 2Eluting fraction 1 + Eluting fraction 273BUSINESS.33535339.1

[0253] Example 1 (T-23 and 1-24)Step 1 Step 2 Step 3 Eluting fraction 1 +Eluting fraction 2

[0254] Step 1. To a stirred solution of 4-chlorothieno[3,2- ]pyrimidine (0.15 g, 0.88 mmol, 1.0 eq.) and tert-butyl (4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)cyclohex-3-en-l-yl)carbamate (0.28 g, 0.88 mmol, 1.0 eq.) in 1,4-dioxane (1.5 mL, 10 vol) and FLO (0.15 mL, 1 vol) was added tri -potassium phosphate (K3PO4) (0.56 g. 2.64 mmol, 3 eq.). The reaction mixture was purged with nitrogen gas for 15 minutes and Pd(dppf)C12.DCM complex (0.07 g, 0.09 mmol, 0.1 eq.) was added at room temperature. The reaction mixture was further allowed to stir at 100 °C for up to 16 h until reaction completion. The completion of reaction was monitored by TLC using 80 % ethyl acetate in hexane and LCMS analysis. The reaction mixture was quenched with H2O (20 mL) and extracted with ethyl acetate (2 x 20 mL). Tire combined organic layers were dried over sodium sulphate and concentrated under a high vacuum. The obtained crude material was purified by manual column chromatography on silica gel using 30 % ethyl acetate in hexane as eluent to obtain tert-butyl (4-(thieno[3,2-d]pyrimidin-4-yl)cyclohex-3-en-l-yl)carbamate (0.2 g, 69 %). LCMS (m / z): 332.2 [M+H]+.

[0255] Step 2. To a stirred solution of tert-butyl (4-(thicno|3.2- |pynmidin-4-yl)cyclohcx-3-cn- l - yl)carbamate (0.2 g, 0.60 mmol, 1.0 eq.) in dichloromethane (2.0 mL, 10 vol) was added 4 M hydrochloric acid in 1,4-dioxane ( 1.0 mL. 5 vol) at 0 °C. The resulting mixture was stirred at room temperature for up to 3 h until reaction completion. The completion of reaction was monitored by TLC using 5 % methanol in di chloromethane and LCMS analysis. The reaction mixture was concentrated under reduced pressure. The isolated solid material was further triturated with diethyl ether (2 x 5 mL) and dried in vacuo to obtain 4- (thieno[3,2-d]pyrimidin-4-yl)cyclohex-3-en-l-amine hydrochloride (0.12 g, 74%). LCMS (m / z): 232.16 [M+H]+.

[0256] Step 3. The isolated racemic material of 4-(thieno[3,2-<7]pyrimidin-4-yl)cyclohex-3-en-l- amine hydrochloride (0.12 g) was submitted to chiral prep HPLC purification (Column: CHIRALPAK IG (250mm x 50mm x 5pm; Mobile Phase A: Liquid CO2, Mobile Phase B: 0.1% methanolic ammonia in methanol-acetonitrile (50-50); Flow rate: 150 mL / min; Gradient: 55 % A to 55 % A in 30 mins; Wave74BUSINESS.33535339.1Length: 210 nm; RTl(min) 16.3; RT2(min): 22.8; Sample Solvent: Methanol; Sample Loading: 10 mg, Number Of Runs: 12).

[0257] Eluting fraction 1: 4-(thicno[3,2-d]pyrimidin-4-yl)cyclohcx-3-cn-l-aminc (1-24) (24.7 mg, light yellow solid). LCMS (m / z): 232.2 [M+H]+; 'H NMR (400 MHz, DMSO-de): 8 9.13 (s, 1H). 8.48 (d, J = 5.2 Hz, 1H). 7.65 (d, J = 5.6 Hz, 1H), 6.92-6.90 (m. 1H), 3.03-3.00 (m, 1H), 2.87-2.79 (m, 1H), 2.63- 2.55 (m, 2H), 2. 12-2.04 (m, 1H), 1.96-1.90 (m, 1H), 1.52-1.47 (m, 1H). (-NH2proton is not distinguishable).

[0258] Eluting fraction 2: 4-(thieno[3,2-d]pyrimidin-4-yl)cyclohex-3-en-l-amine (1-23) (25.3 mg, light yellow solid). LCMS (m / z): 232.2 [M+H]+; 'H NMR (400 MHz, DMSO-de): 8 9.12 (s, 1H), 8.47 (d, J = 5.2 Hz, 1H), 7.65 (d, J = 5.6 Hz, 1H), 6.92-6.90 (m, 1H), 3.02-2.95 (m, 1H), 2.86-2.79 (m, 1H), 2.64- 2.55 (m, 2H), 2.09-2.02 (m, 1H). 1.95-1.89 (m. 1H), 1.51-1.45 (m, 1H). (-NH2proton is not distinguishable).Additional Exemplary Compounds Prepared via Example 1 Methods75BUSINESS.33535339.176BUSINESS.33535339.177BUSINESS.33535339.178BUSINESS.33535339.179BUSINESS.33535339.1

[0259] Example 2 (T-31 a & 1-31 b)

[0260] Step 1. The racemic material of tcrt-but l (4-(4, 4.5, 5 -tetramethyl- 1,3.2-dioxaborolan-2- yl)cyclohex-3-en-l-yl)carbamate (10.0 g) was submitted to chiral prep HPLC purification to separate the enantiomers. Eluting fraction 1: 4.1 g; Eluting fraction 2: 3.9 g. Analytical chiral HPLC: Column CHIRALPAK IG-3 (100x3mm, 3 pm); Solvent: 0.1% methanolic ammonia in MeOH:ACN (50:50); Injection volume: 2 pL; Wavelength: 230 nm; Eluting fraction 1 : retention time 0.858 min; Eluting fraction2: retention time 0.953 min.

[0261] To a stirred solution of 7-chlorothieno[3,2-b]pyridine-2 -carbonitrile (0.05 g, 0.3 mmol, 1.0 eq.) and the first eluting fraction of the chirally-separated tert-butyl (4-(4,4,5.5-tetramethyl-l,3,2-dioxaborolan- 2-yl)cyclohex-3-en-l-yl)carbamate (0.1 g, 0.3 mmol, 1.2 eq.) in 1, 4 dioxane (0.9 mb, 18 vol) and water (0.1 mL, 2 vol) was added tri-potassium phosphate (K3PO4) (0.163 g, 0.768 mmol, 3 eq.). The reaction mixture was purged with nitrogen gas for 10 minutes and Pd(dppf)C12.DCM complex (0.02 g, 0.03 mmol, 0.1 eq.) was added at room temperature. Tire reaction mixture was allowed to stir at 100 °C for 4h. The completion of reaction was monitored by TLC using 30% ethyl acetate in hexane and LCMS analysis. Tire reaction mixture was quenched with water (20 mL) and extracted with ethyl acetate (2 X 10 mL). The80BUSINESS.33535339.1combined organic layers were dried over sodium sulphate and concentrated under high vacuum to obtain the crude residue. The crude material was purified by flash column chromatography on silica gel using 17% ethyl acetate in hexane as eluent to afford tcrt-butyl (4-(2-cyanothieno[3,2-b]pyridin-7-yl)cyclohex-3-en- l-yl)carbamate (Qty: 0.05 g, 55%). LCMS (m / z): 356.2 [M+H]+.

[0262] Step 2. To a stirred solution of 7-chlorothicno|3.2-b|pyndinc-2-carbonitrilc (0.05 g, 0.3 mmol, 1.0 eq.) and the second eluting fraction of the chirally-separated tert-butyl (4-(4,4,5,5-tetramethyl- l,3,2-dioxaborolan-2-yl)cyclohex-3-en-l-yl)carbamate (0.1 g, 0.3 mmol, 1.2 eq.) in 1, 4 dioxane (0.9 mL, 18 vol) and water (0.1 mL, 2 vol) was added tri-potassium phosphate (K3PO4) (0.163 g, 0.768 mmol, 3 eq.). The reaction mixture was purged with nitrogen gas for 10 minutes and Pd(dppf)C12.DCM complex (0.02 g, 0.03 mmol, 0.1 eq.) was added at room temperature. Tire reaction mixture was allowed to stir at 100 °C for 4h. The completion of reaction was monitored by TLC using 30% ethyl acetate in hexane and LCMS analysis. The reaction mixture was quenched with water (20 mL) and extracted with ethyl acetate (2 X 10 mL). The combined organic layers were dried over sodium sulphate and concentrated under high vacuum to obtain the crude residue. The crude material was purified by flash column chromatography on silica gel using 17% ethyl acetate in hexane as eluent to afford tert-butyl (4-(2-cyanothieno[3.2-b]pyridin- 7-yl)cyclohex-3-en-l-yl)carbamate (Qty: 0.035 g, 38%). LCMS (m / z): 356.3 [M+H]+.

[0263] Step 3. In a vial were added tert-butyl (4-(2-cyanothieno[3.2-b]pyridin-7-yl)cyclohex-3-en-l- yl)carbamate, prepared from the first eluting fraction as in step 1 (0.05 g, 0.1 mmol, 1.0 eq.) and formic acid (0.5 mL, 10 vol). The resulting mixture was allowed to stir at 60°C for Ih. The completion of the reaction was monitored by TLC using 5% methanol in dichloromcthanc and LCMS analysis. Tire reaction mixture was concentrated under reduce pressure to obtain the crude residue. The crude material was submitted to preparative HPLC purification to afford a pure fraction. The fraction was lyophilized to afford 7-(4-aminocyclohex-l-en-l-yl)thieno[3,2-b]pyridine-2 -carbonitrile formate (I-31a) (Qty: 0.022 g, 53%) as a yellow' sticky solid. LCMS (m / z): 256.1 [M+H]+; Analytical chiral HPLC: Column CHIRALPAK IG-3 (100x3mm, 3 pm), Solvent: 0.1% methanolic ammonia in IPA:ACN (50:50), Injection volume: 3 pL, Retention time: 2.680 min, Wavelength: 250 nm; IH NMR (400 MHz, DMSO): 5 8.83 (d, J = 5.0 Hz, IH), 8.54 (s, IH), 8.40 (s, IH). 7.53 (d, J = 5.0 Hz, IH). 6.45 (s, IH), 3.24 (bs, IH), 2.70-2.60 (m, 3H), 2.27- 2.20 (m. IH), 2.07-2.04 (m, IH), 1.71-1.68 (m, IH).

[0264] Step 4. In a vial were added tert-butyl (4-(2-cyanothieno[3,2-b]pyridin-7-yl)cyclohex-3-en-l- yl)carbamate, prepared from the second eluting fraction as in step 2 (0.035 g, 0.098 mmol, 1.0 eq.) and fomric acid (0.35 mL, 10 vol). The resulting mixture was allowed to stir at 60 °C for Ih. The completion of the reaction was monitored by TLC using 5% methanol in dichloromethane and LCMS analysis. Hie reaction mixture was concentrated under reduce pressure to obtain the crude residue. The crude material was submitted to preparative HPLC purification to afford the pure fraction. The fraction was lyophilized to81BUSINESS.33535339.1obtain 7-(4-aminocyclohex-l-en-l-yl)thieno[3,2-b]pyridine-2-carbonitrile formate (I-31b) (Qty: 0.006 g, 20%) as brown sticky solid. LCMS (m / z): 256.2 [M+H]+; Analytical chiral HPLC: Column CHIRALPAK IG-3 (100x3mm, 3 gm), Solvent: 0.1% methanolic ammonia in IPA:ACN (50:50), Injection volume: 8 gL, Retention time: 3.835 mm, Wavelength: 240 nm; 1H NMR (400 MHz, DMSO): 5 8.84 (d, J = 5.0 Hz, 1H), 8.58 (s, 1H), 8.40 (s, 1H). 7.53 (d, J = 5.0 Hz, 1H). 6.45 (s, 1H), 3.24 (bs, 1H), 2.62-2.59 (m, 3H), 2.30- 2.15 (m. 1H), 2.07-2.04 (m, 1H), 1.80-1.60 (m, 1H).

[0265] Example 3 (I-32a & I-32b),82BUSINESS.33535339.1410095-003WQ (221371)

[0266] Step 1. To a stirred solution of 6-bromo-4-chlorothieno[3,2-d]pyrimidine (1.0 g, 4.0 mmol, 1.0 eq.) and ethyltrifluoro-4-borane potassium salt (1.09 g, 8.02 mmol, 2.0 eq.) in a solution of toluene (10 mL, 10 vol), water (2.5 mL, 2.5 vol) and tetrahydrofuran (2.5 mL, 2.5 vol) was added caesium carbonate (CS2CO3) (3.91 g, 12.0 mmol, 3.0 eq.). The reaction mixture was purged with nitrogen gas for 10 minutes and PdC12(dppf (0.38 g, 0.47 mmol, 0.1 eq.) was added at room temperature. Tire reaction mixture was allowed to stir at 100°C for 16h. The completion of the reaction was monitored by TLC using 30% ethyl acetate in hexane and LCMS analysis. The reaction mixture was quenched with water (100 mL) and extracted with ethyl acetate (2 X 100 mL). The combined organic layers were dried over anhydrous sodium sulphate and concentrated under reduced pressure to obtain the crude material. The crude residue was purified by flash column chromatography on silica gel using 25% ethyl acetate in hexane as an eluent to afford 4-chloro-6-ethylthieno[3.2-d] pyrimidine (Qty: 0.2 g, yield:25%) as a white solid. LCMS (m / z): 199.0 [M+H]+.

[0267] Step 2. To a stirred solution of 4-chloro-6-ethylthieno[3,2-d]pyrimidine (0.1 g, 0.50 mmol, 1.0 eq.) and the first eluting fraction of the chirally-separated tert-butyl (4-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)cyclohex-3-en-l-yl)carbamate (see example method 2, 0.24 g, 0.76 mmol, 1.5 eq.) in 1,4-dioxane (1 mL, 10 vol) and water (0. 1 mL, 1 vol) was added tri-potassium phosphate (K3PO4) (0.32 g, 1.5 mmoL 3 eq.). The reaction mixture was purged with nitrogen gas for 10 minutes and Pd(dppf)C12.DCM complex (0.04 g, 0.05 mmol, 0. 1 eq.) was added at room temperature. The reaction mixture was allowed to stir at 100°C for 16h. The completion of reaction was monitored by TLC using 30% ethyl acetate in hexane and LCMS analysis. After completion of the reaction, the reaction mixture was quenched with water (50 mL) and extracted with ethyl acetate (2 X 50 mL). The combined organic layers were dried over sodium sulphate and concentrated under high vacuum to obtain the crude residue. The crude material was purified by flash column chromatography on silica gel using 25% ethyl acetate in hexane as eluent to tert-butyl 4- (6-ethylthieno[3,2-d] pyrimidin-4-yl) cyclohex-3 -en-l-yl carbamate (Qty: 0.07 g, 39%). LCMS (m / z): 360.2 [M+H]+.

[0268] Step 3. To a stirred solution of 4-chloro-6-ethylthieno[3,2-d]pyrimidine (0.1 g, 0.5 mmol, 1.0 eq.) and the second eluting fraction of the chirally-separated tert-butyl (4-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)cyclohex-3-en-l-yl)carbamate (see example method 2, 0.24 g, 0.76 mmol, 1.5 eq.) in 1,4-dioxane (1 mL, 10 vol) and water (0. 1 mL, 1 vol) was added tri-potassium phosphate (K3PO4) (0.32 g, 1.5 mmol, 3 eq.). The reaction mixture was purged with nitrogen gas for 10 minutes and Pd(dppf)C12.DCM complex (0.04 g, 0.05 mmol, 0. 1 eq.) was added at room temperature. Tire reaction mixture was allowed to stir at 100°C for 16h. The completion of reaction was monitored by TLC using 30% ethyl acetate in hexane and LCMS analysis. Tire reaction mixture quenched with water (50 mL) and extracted with ethyl acetate (2 X 50 mL). The combined organic layers were dried over sodium sulphate and concentrated under high83BUSINESS.33535339.1vacuum to obtain the crude residue. The obtained crude material was purified by flash column chromatography on silica gel using 23% ethyl acetate in hexane as eluent to get tert-butyl 4-(6- ethylthieno[3,2-d] pyrimidin-4-yl) cyclohex-3-en-l-yl carbamate (Qty: 0.14 g, 77%). LCMS (m / z): 360.2 [M+H]+.

[0269] Step 4. To a stirred solution of tert-butyl 4-(6-ethylthieno[3,2-d] pyrimidin-4-yl) cyclohex-3- en-l-yl carbamate prepared from the first eluting fraction as in step 2 (0.07 g, 0.2 mmol, 1.0 eq.) in dichloromethane (0.7 mL, 10 vol) was added 4M hydrochloric acid in 1,4-dioxane (0.35 mL, 5 vol) at 0°C. The resulting mixture was allowed to stir at room temperature for 3h. The completion of reaction was monitored by TLC using 5% methanol in dichloromethane and LCMS analysis. The reaction mixture was concentrated under reduce pressure. Hie isolated solid material was further triturated with diethyl ether (3 X 10 mL) and dried in vacuo to get 4-(6-ethylthieno[3,2-d] pyrimidin-4-yl) cyclohex-3 -en-1 -amine hydrochloride (I-32a) (Qty: 0.05 g, Yield: 86%) as brown sticky solid. LCMS (m / z): 260.3 [M+H]+. Analytical chiral HPLC: Column CHIRALPAK IG-3 (100x3mm, 3 pm), Solvent: 0.1% methanolic ammonia in MeOH:ACN (50:50), Injection volume: 4 pL, Retention time: 2.440 min, Wavelength: 235 nm; lH NMR (400 MHz, DMSO): 5 9.07 (s, 1H), 8.16 (s, 3H), 7.42 (s, 1H), 6.83 (s, 1H), 3.41 (s, 1H). 3.04 (q, J = 7.5 Hz, 2H), 2.89 (d, J = 17.2 Hz, 1H), 2.77-2.67 (m, 2H). 2.16-2.13 (m, 1H), 1.79-1.57 (m. 2H), 1.36 (t, J = 7.5 Hz, 3H).

[0270] Step 5. To a stirred solution of tert-butyl 4-(6-ethylthieno[3,2-d] pyrimidin-4-yl) cyclohex-3- en-l-yl carbamate prepared from the second eluting fraction as in step 3 (0.14 g, 0.39 mmol, 1.0 eq.) in dichloromcthanc (1.4 mL, 10 vol) was added 4M hydrochloric acid in 1, 4 dioxane (0.7 mL, 5 vol) at 0°C. The resulting mixture was allowed to stir at room temperature for 3h. The completion of reaction w as monitored by TLC using 5% methanol in di chloromethane and LCMS analysis. The reaction mixture was concentrated under reduce pressure. The isolated solid material was further triturated with diethyl ether (3 X 10 mL) and dried in vacuo to get 4-(6-ethylthieno[3,2-d] pyrimidin-4-yl) cyclohex-3 -en-1 -amine hydrochloride (I-32b) (Qty: 0.08 g, Yield: 69%) as brown sticky solid. LCMS (m / z): 260.2 [M+H]+. Analytical chiral HPLC: Column CHIRALPAK IG-3 (100x3mm, 3 pm), Solvent: 0.1% methanolic ammonia in MeOH:ACN (50:50), Injection volume: 4 pL, Retention time: 2.577 min, Wavelength: 235 nm; 1H NMR (400 MHz, DMSO): 5 9.07 (s. 1H), 8.14 (s, 3H), 7.42 (s, 1H). 6.83 (s. 1H), 3.42 (br s, 1H), 3.05 (q, J = 7.5, 2H), 2.89 (d, J = 16.8 Hz, 1H), 2.77-2.60 (m, 2H), 2.49-2.40 (m, 1H), 2.15 (d, J = 7.0 Hz, 1H), 1.79-1.75 (m, 1H), 1.36 (t, J = 7.5 Hz, 3H).84BUSINESS.33535339.1410095-003WQ (221371)

[0271] Example 4 (1-36 & 1-37) i) n-BuLi, THF, NH2NH2OH, -78°C 2h MeOH, 3h,

[0272] Step 1. To a stirred solution of 4-methylthiophene-2-carboxylic acid (3.0 g, 21 mmol, 1.0 eq.) in tetrahydro furan (60 mL, 20 vol) was added n-BuLi (1.6 M in hexane) (32.97 mL, 53.59 mmol, 2.5 eq.) at -78°C. The reaction mixture was allowed to stir at -78 °C for 2 h and dimethylformamide (7.71 g, 106 85BUSINESS.33535339.1410095-003WQ (221371) mmol, 5.0 eq.) was added. The reaction mixture was allowed to stir at room temperature for 16 h. The completion of reaction was monitored by TLC using 20% ethyl acetate in hexane and LCMS analysis. The reaction mixture was quenched with ice cold water (100 mL) and extracted with ethyl acetate (2 X 70 mL). Tire aqueous layer was acidified using aqueous hydrochloric acid solution and extracted with ethyl acetate (3 X 80 mL). The combined organic layers were dried over anhydrous sodium sulphate and concentrated under reduced pressure to obtain the crude material. The material was purified by flash column chromatography on silica gel using 14% ethyl acetate in hexane as an eluent to afford 3-formyl-4- methylthiophene-2-carboxylic acid) (Qty: 1.57 g, yield: 44%) as a light yellow solid. LCMS (m / z): 169.1 [M-H]-.

[0273] Step 2. To a stirred solution of 3-formyl-4-methylthiophene-2-carboxylic acid (1.5 g, 8.8 mmol. 1.0 eq.) in methanol (15 mL, 10 vol) was added hydrazine hydrate (1.1 g, 22 mmol, 2.5 eq.). The reaction mixture was allowed to stir under reflux conditions for 3 h. The completion of the reaction was monitored by TLC using 20% ethyl acetate in hexane and LCMS analysis. The reaction mixture was concentrated under high vacuum and quenched with water (40 mL). The precipitated solid was filtered and dried well under reduced pressure. The isolated solid material was further triturated with n-pentane (2 X 20 mL) and dried well in vacuo to afford 3-methylthieno[2,3-d] pyridazin-7(7aH)-one and 3-methylthieno[2,3- d] pyridazin-7-ol (Qty:0.85 g, yield: 58%) as off white solid. LCMS (m / z): 167.0 [M+H]+.

[0274] Step 3. To a stirred solution of 3-methylthieno[2,3-d] pyridazin-7(7aH)-one and 3- methylthieno[2,3-d] pyridazin-7-ol (0.75 g, 4.5 mmol, 1.0 eq.) in acetonitrile (15 mL, 20 vol.) was added phosphorous oxy-bromidc (POBr3) (1.94, 6.77 mmol, 1.5 cq.) at 0 °C. Tire reaction mixture was allowed to stir at 80°C for 16 h. Hie completion of reaction was monitored by TLC using 40% ethyl acetate in hexane and LCMS analysis. The reaction mixture was quenched with water (70 mL) and extracted with ethyl acetate (2 X 50 mL). The combined organic layers were dried over anhydrous sodium sulphate and concentrated under reduced pressure to obtain the crude material. The material was purified by flash column chromatography on silica gel using 32% ethyl acetate in hexane as an eluent to get 7-bromo-3- mcthylthicno[2,3-d] pyridazinc (Qty: 0.4 g, yield: 39%) as off white solid. LCMS (m / z): 228.9 [M+H]+.

[0275] Step 4. To a stirred solution of 7-bromo-3-methylthieno[2.3-d]pyridazine (0.08 g, 0.4 mmol, 1.0 eq.) and the first eluting fraction of the chirally-separated tert-butyl (4-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)cyclohex-3-en-l-yl)carbamate (see example method 2, 0.014 g, 0.42 mmol, 1.2 eq.) in 1,4-dioxane (1.6 mL, 20 vol) and water (0.1 mL, 1 vol) was added tri-potassium phosphate (K3PO ) (0.11 g, 0.53 mmol, 1.5 cq.). The reaction mixture was purged with nitrogen gas for 10 minutes and Pd(dppf)C12.DCM complex (0.06 g, 0.07 mmol, 0.2 eq.) was added at room temperature. The reaction mixture was allowed to stir at 100°C for Ih. The completion of the reaction was monitored by TLC using 70% ethyl acetate in hexane and LCMS analysis. The reaction mixture was quenched with water (35 mL)86BUSINESS.33535339.1410095-003WQ (221371) and extracted with ethyl acetate (2 X 30 mL). The combined organic layers were dried over sodium sulphate and concentrated under high vacuum to obtain the crude material. The material was purified by flash column chromatography on silica gel using 52% ethyl acetate in hexane as eluent to afford tert-butyl (4-(3- methylthieno[2,3-d] pyridazin-7-yl) cyclohex-3 -en-l-yl) carbamate (Qty: 0.095 g, 78%) as off white solid. LCMS (m / z): 346.1 [M+H]+.

[0276] Step 5. To a stirred solution of 7-bromo-3-methylthieno[2,3-d]pyridazine (0.08 g, 0.4 mmol, 1.0 eq.) and the second eluting fraction of the chirally-separated tert-butyl (4-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)cyclohex-3-en-l-yl)carbamate (see example method 2, 0.014 g, 0.42 mmol, 1.2 eq.) in 1,4-dioxane (1.6 mL, 20 vol) and water (0.1 mL, 1 vol) was added tri-potassium phosphate (K3PO4) (0.11 g, 0.53 mmol, 1.5 eq.). The reaction mixture was purged with nitrogen gas for 10 minutes and Pd(dppf)C12.DCM complex (0.06 g, 0.07 mmol, 0.2 eq.) was added at room temperature. The reaction mixture was allowed to stir at 100 °C for Ih. The completion of reaction was monitored by TLC using 70% ethyl acetate in hexane and LCMS analysis. After completion of the reaction, the reaction mixture was quenched with water (30 mL) and extracted with ethyl acetate (2 X 35 mL). The combined organic layers were dried over sodium sulphate and concentrated under high vacuum to obtain the crude residue. The crude material was purified by flash column chromatography on silica gel using 50% ethyl acetate in hexane as eluent to tert-butyl (4-(3-methylthieno[2,3-d] pyridazin-7-yl) cyclohex-3 -en-l-yl) carbamate (Qty: 0.09 g, 74%) as off white solid. LCMS (m / z): 346.1 [M+H]+.

[0277] Step 6. To a stirred solution of tert-butyl (4-(3-methylthieno[2,3-d] pyridazin-7-yl) cyclohex- 3-cn-l-yl) carbamate, prepared from the first eluting fraction as in step 4 (0.09 g, 0.3 mmol, 1.0 eq.) in dichloromethane (1.8 mL, 20 vol) was added 4M hydrochloric acid in 1,4-dioxane (0.4 mL, cat.) at 0°C. The resulting reaction mixture was allowed to stir at room temperature for 2 h. The completion of reaction was monitored by TLC using 90% ethyl acetate in hexane and LCMS analysis. The reaction mixture was concentrated under reduce pressure. The isolated solid material was further triturated with diethyl ether (2 X 10 mL) to get 4-(3-methylthieno[2,3-d] pyridazin-7-yl) cyclohex-3-en- 1 -amine hydrochloride (1-36) (Qty: 0.051 g, Yield: 69%) as off white solid. LCMS (m / z): 246. 1 [M+H]+. Analytical chiral HPLC: Column CHIRALPAK IG-3 (100x3mm, 3 pm), Solvent: 0.1% methanolic ammonia in MeOH:ACN (50:50), Injection volume: 2 pL, Retention time: 2.605 min, Wavelength: 225 nm; IH NMR (400 MHz, DMSO): 5 9.78 (s, IH), 8.26 (s, 3H), 8.17 (s, IH), 6.79 (s, IH), 3.45 (s, IH), 2.99-2.90 (m, IH), 2.85-2.20 (m, 2H), 2.58 (s, 3H), 2.50-2.40 (m, IH), 2.25-2.15 (m, IH), 1.89-1.79 (m, IH).

[0278] Step 7. To a stirred solution of tert-butyl (4-(3-methylthieno[2,3-d] pyridazin-7-yl) cyclohex- 3-en-l-yl) carbamate, prepared from the second eluting fraction as in step 5 (0.09 g, 0.3 mmol, 1.0 eq.) in dichloromethane (1.8 mL. 20 vol) was added 4M hydrochloric acid in 1,4-dioxane (0.4 mL, catalytic) at 0°C. The resulting mixture was allowed to stir at room temperature for 2h. The completion of the reaction87BUSINESS.33535339.1410095-003WQ (221371) was monitored by TLC using 90% ethyl acetate in hexane and LCMS analysis. The reaction mixture was concentrated under reduce pressure. The isolated solid material was further triturated with diethyl ether (2 X 15 mL) to get 4-(3-methylthieno[2,3-d] pyridazin-7-yl) cyclohex-3-en- 1 -amine hydrochloride (1-37) (Qty: 0.045 g, Yield: 61%) as off white solid. LCMS (m / z): 246.1 [M+H]+. Analytical chiral HPLC: Column CHIRALPAK IG-3 (100x3mm, 3 pm), Solvent: 0.1% methanolic ammonia in MeOH:ACN (50:50), Injection volume: 3 pL, Retention time: 2.750 min, Wavelength: 225 nm; 1H NMR (400 MHz, DMSO): 5 9.78 (s, 1H), 8.27 (s, 3H), 8.17 (s, 1H), 6.79 (s, 1H), 3.45 (s, 1H), 2.96-2.90 (m, 1H), 2.79-2.70 (m, 2H), 2.58 (s, 3H), 2.50-2.40 (m, 1H), 2.25-2.15 (m, 2H), 1.89-1.80 (m, 1H).88BUSINESS.33535339.1

[0279] Example 5 (T-39 & 1-40)PdCI2(dppf).DCM, 1,4-dioxane / H20 100°C, 1-16h89BUSINESS.33535339.1

[0280] Step 1. To a stirred solution of 5-bromonicotinic acid (10.0 g, 49.5 mmol, 1.0 eq.) in tetrahydrofuran (100 mL, 10 vol) was added lithium diisopropylamide (LDA) (2M in tetrahydrofuran) (58.41 mL, 116.8 mmol, 2.36 eq.) at -78 °C. The reaction mixture was stirred at -78 °C for 2.5 h and 1,2- dibromo-l,l,2,2-tetrachloroethane (20.14 g. 61.87 mmol, 1.25 eq.) was added. Hie reaction mixture was further allowed to stir at -78°C for 2h. The completion of reaction was monitored by TLC using 10% methanol in dichloromethane and LCMS analysis. The reaction mixture quenched with cold water solution (500 mL) and extracted with ethyl acetate (2 X 300 mL) to remove non-polar impurities. The aqueous layer was acidified to pH 3 using concentrated hydrochloric acid in dropwise manner. The precipitated solid was filtered and dried well to get the product as 4, 5 -dibromonicotinic acid as white solid (Qty: 10 g, 72%). LCMS (m / z): 281.8 [M+H]+.

[0281] Step 2. To a stirred solution of 4.5-dibromonicotinic acid (9.0 g. 32 mmol, 1 eq.) in ethyl acetate (90 mL, 10 vol) was added N,N-diisopropylethylamine (16.5 mL, 96.0 mmol, 3.0 eq.) and stirred for 10 minutes. To the above reaction mixture N,O-dimethylhydroxylammonium chloride (4.68 g, 48.0 mmol, 1.5 eq.) and 1-propanephosphonic acid cyclic anhydride (50% in ethyl acetate) were added at room temperature. The reaction mixture was allowed to stir at room temperature for 16h. The completion of reaction was monitored by TLC using 30% ethyl acetate in hexane and LCMS analysis. The reaction mixture was quenched with water (750 mL) and extracted with ethyl acetate (2 X 500 mL). The combined organic layers were dried over anhydrous sodium sulphate and concentrated under reduced pressure to obtain the crude residue. The crude material was purified by flash column chromatography on silica gel using 13% ethyl acetate in hexane as eluent to afford 4,5-dibromo-N-mcthoxy-N-mcthylnicotinamidc (Qty: 9.2 g, 89%). LCMS (m / z): 324.8 [M+H]+.

[0282] Step 3. To a stirred solution of 4,5-dibromo-N-methoxy-N-methylnicotinamide (9.0 g, 27 mmol, 1.0 eq.) in N,N-dimethylformamide (90 mL, 10 vol) were added K2CO3 (4.6 g, 33 mmol, 1.2 eq.) and 2-methylpropane-2-thiol (3.05 mL, 27.0 mmol, 1.0 eq.) at room temperature . The reaction mixture was allowed to stir at 130°C for 20 h. Tire completion of reaction was monitored by TLC using 30% ethyl acetate in hexane and LCMS analysis. Tire reaction mixture was quenched with ice cold water (1000 mL) and extracted with ethyl acetate (2 X 500 mL). Tire combined organic layers were dried over sodium sulphate and concentrated under reduced pressure to obtain the crude material. The material was purified by flash column chromatography on silica gel using 20% ethyl acetate in hexane as eluent. The isolated material was further purified by reverse phase flash column chromatography using 55% acetonitrile in water as eluent. The isolated pure fractions were concentrated under reduced pressure followed by lyophilization to get 5-bromo-4-(tert-butylthio)-N-methoxy-N-methylnicotinamide (Qty: 6.0 g, 65%). LCMS (m / z): 334.9 [M+H]+.90BUSINESS.33535339.1

[0283] Step 4. To a stirred solution of 5-bromo-4-(tert-butylthio)-N-methoxy-N-methylnicotinamide (4.5 g, 14 mmol, 1.0 eq.) in toluene (90 mL, 20 vol) was added diisobutylaluminum hydride (IM (-20%) solution in toluene) (DIBAL-H) (16.2 mL, 16.2 mmol, 1.2 eq.) at -50 °C. The reaction mixture was allowed to stir at room temperature for 2h. The completion of reaction was monitored by TLC using 30% ethyl acetate in hexane and LCMS analysis. The reaction mixture was quenched with ice cold water (500 mL) and extracted with ethyl acetate (2 X 250 mL). The combined organic layers were dried over sodium sulphate and concentrated under reduced pressure to afford the erode material. The material was purified by flash column chromatography on silica gel using 25% ethyl acetate in hexane as eluent to afford 5- bromo-4-(tert-butylthio)nicotinaldehyde (Qty: 1.41 g, 38%). LCMS (m / z): 274.0 [M+H]+.

[0284] Step 5. To a stirred solution of 5-bromo-4-(tert-butylthio)nicotinaldehyde (1.4 g, 5.1 mmol, 1.0 eq.) in 2-propanol (42 mL. 30 vol): water (14 mL, 10 vol) was added hydroxylamine hydrochloride ( 1.7 g, 69 mmol, 5 eq.) at room temperature. The reaction mixture was allowed to stir at 90°C for 4h. The completion of reaction was monitored by TLC using 30% ethyl acetate in hexane and LCMS analysis. The reaction mixture was concentrated to remove the solvent. Hie suspension was quenched with saturated sodium bicarbonate solution (250 mL) and extracted with ethyl acetate (2 X 125 mL). Hie combined organic layers were dried over sodium sulphate and concentrated under reduced pressure to get obtain the crude residue as (E)-5-bromo-4-(tert-butylthio)nicotinaldehyde oxime (Qty: 1.1 g. 74%). The crude material was used as such in the next step without further purification. LCMS (m / z): 289.0 [M+H]+.

[0285] Step 6. To a stirred solution of (E)-5-bromo-4-(tert-butylthio)nicotinaldehyde oxime (1.0 g, 3.5 mmol, 1.0 eq.) in 1-butanol (20 mL, 20 vol) was added p-toluenesulfonic acid (0.658 g, 3.46 mmol, 1 eq.) at room temperature. The reaction mixture was allowed to stir at 100 °C for 16 h. The completion of reaction was monitored by TLC using 20% ethyl acetate in hexane and LCMS analysis. After completion of the reaction, the reaction mixture was quenched with water (500 mL) and extracted with ethyl acetate (2 X 250 mL). The combined organic layers were dried over sodium sulphate and concentrated under reduced pressure to obtain the crude material. Hie material was purified by flash column chromatography on silica gel using 16% ethyl acetate in hexane as eluent to afford 7-bromoisothiazolo[4,5-c]pyridine as white solid (Qty: 0.6 g, 81%). LCMS (m / z): 215.0 [M+H]+.

[0286] Step 7. To a stirred solution of 7-bromoisothiazolo[4,5-c]pyridine (0.07 g, 0.3 mmol, 1.0 eq.) and the first eluting fraction ofthe chirally-separated tert-butyl (4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan- 2-yl)cyclohex-3-en-l-yl)carbamate (see example method 2, 0.157 g, 0.488 mmol, 1.5 eq.) in 1, 4 dioxane (1.4 mL, 20 vol) and water (0.07 mL, 1 vol) was added tri-potassium phosphate (K3PO4) (0.207 g, 0.976 mmol. 3 eq.). Hie reaction mixture was purged with nitrogen gas for 10 minutes and Pd(dppf)CL.DCM complex (0.03 g, 0.03 mmol, 0. 1 eq.) was added at room temperature. The reaction mixture was allowed to stir at 100°C for 3h. The completion of reaction was monitored by TLC using 40% ethyl acetate in hexane91BUSINESS.33535339.1and LCMS analysis. The reaction mixture quenched with water (30 mL) and extracted with ethyl acetate (2 X 25 mL). The combined organic layers were dried over sodium sulphate and concentrated under reduced pressure to obtain the crude material. The material was purified by flash column chromatography on silica gel using 30% ethyl acetate in hexane as eluent to afford tert-butyl (4-(isothiazolo[4,5-c]pyridin-7- yl)cyclohex-3-en-l-yl)carbamate (Qty: 0.09 g. 83%). LCMS (m / z): 332.1 [M+H]+.

[0287] Step 8. To a stirred solution of 7-bromoisothiazolo [4,5 -c]pyri dine (0.07 g, 0.3 mmol, 1.0 eq.) and the second eluting fraction of the chirally-separated tert-butyl (4-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)cyclohex-3-en-l-yl)carbamate (see example method 2, 0.157 g, 0.488 mmol, 1.5 eq.) in 1, 4 dioxane (1.4 mL, 20 vol) and water (0.07 mL, 1 vol) was added tri-potassium phosphate (K3PO4) (0.207 g, 0.976 mmol, 3 eq.). The reaction mixture was purged with nitrogen gas for 10 minutes and Pd(dppf)C12.DCM complex (0.03 g, 0.03 mmol, 0.1 eq.) was added at room temperature. The reaction mixture was allowed to stir at 100 °C for 3 h. The completion of reaction was monitored by TLC using 40% ethyl acetate in hexane and LCMS analysis. The reaction mixture was quenched with water (30 mL) and extracted with ethyl acetate (2 X 25 mL). The combined organic layers were dried over sodium sulphate and concentrated under reduced pressure to obtain the crude material. The material was purified by flash column chromatography on silica gel using 30% ethyl acetate in hexane as eluent to afford tert-butyl (4- (isothiazolo[4.5-c]pyridin-7-yl)cyclohex-3-en-l-yl)carbamate (Qty: 0.09 g, 83%). LCMS (m / z): 332.1 [M+H]+.

[0288] Step 9. To a stirred solution of tert-butyl (4-(isothiazolo[4,5-c]pyridin-7-yl)cyclohex-3-en-l- yl)carbamatc prepared from the first eluting fraction as in step 7 (0.08 g, 0.2 mmol, 1.0 cq.) in dichloromethane (1.6 mL, 20 vol) was added 4M hydrochloric acid in 1, 4 dioxane (0.4 mL, 5 vol) at 0 °C. The reaction mixture was allowed to stir at room temperature for 16 h. The completion of reaction was monitored by TLC using 10% methanol in dichloromethane and LCMS analysis. The reaction mixture was concentrated under reduce pressure to obtain the crude material. The crude residue was triturated with diethyl ether (4 x 20 mL) and dried well under vacuum to get 4-(isothiazolo[4,5-c]pyridin-7-yl)cyclohex- 3-cn-l-aminc hydrochloride (1-39) (Qty:0.061 g, 95%) as white solid. LCMS (m / z): 232.1 [M+H]+. Analytical chiral HPLC: Column CHIRALPAK IG-3 (100x3mm, 3 pm), Solvent: 0.1% methanolic ammonia in MeOH:ACN (50:50), Injection volume: 4 pL, Retention time: 3.367 min, Wavelength: 218 nm; 1H NMR (400 MHz, DMSO): 5 9.70 (bs, 1H), 9.50 (s, 1H), 8.78 (bs, 1H), 8.34 (s, 3H), 6.36 (s, 1H), 3.41 (s, 1H), 2.73 (s, 3H), 2.50-2.45 (m, 1H), 2.20-2.17 (m, 1H), 1.89-1.84 (m, 1H).

[0289] Step 10. To a stirred solution of tert-butyl (4-(isothiazolo[4,5-c]pyridin-7-yl)cyclohex-3-en-l- yljcarbamate prepared from the second eluting fraction as in step 8 (0.08 g, 0.2 mmol, 1.0 eq.) in dichloromethane (1.6 mL, 20 vol) was added 4M hydrochloric acid in 1,4-dioxane (0.4 mL. 5 vol) at 0 °C. The reaction mixture was allowed to stir at room temperature for 16 h. The completion of reaction was92BUSINESS.33535339.1410095-003WQ (221371) monitored by TLC using 10% methanol in dichloromethane and LCMS analysis. The reaction mixture was concentrated under reduce pressure to obtain the crude material. The material was triturated with diethyl ether (4 x 20 mL) and dried well under vacuum to get 4-(isothiazolo[4,5-c]pyridin-7-yl)cyclohex-3-en-l- amine hydrochloride (1-40) (Qty:0.061 g. 95%) as white solid. LCMS (m / z): 232.1 [M+H]+. Analytical chiral HPLC: Column CHIRALPAK IG-3 (100x3mm, 3 pm), Solvent: 0.1% methanolic ammonia in MeOH:ACN (50:50), Injection volume: 4 pL. Retention time: 4.109 min. Wavelength: 218 nm; 1H NMR (400 MHz, DMSO): 5 9.56 (s, 1H), 9.48 (s, 1H), 8.70 (s, 1H), 8.29 (s, 3H), 6.34 (s, 1H), 3.42 (s, 1H), 2.74 (s, 3H), 2.51-2.40 (m, 1H), 2.19-2.17 (m, 1H), 1.88-1.84 (m, 1H).

[0290] Example 6 (1-42 & 1-43)93BUSINESS.33535339.1

[0291] Step l. To a stirred solution of 4-bromoisothiazole (2.5 g, 15 mmol, 1 .0 eq.) in tetrahydrofuran (25 mL, 10 vol) was added lithium-diisopropyl amide (LDA) (2M in tetrahydrofuran) (15.24 mL, 30.48 mmol, 2.0 eq.) at -78 °C. The reaction mixture was stirred for 30 minutes and ethyl carbonocyanidatc (1.81 g, 18.3 mmol. 1.2 eq.) was added at -78 °C. Hie reaction mixture was allowed to stir at -78 °C for 30 minutes. The completion of reaction was monitored by TLC using 5% ethyl acetate in hexane and LCMS analysis. The reaction mixture quenched with saturated ammonium chloride solution (500 mL) and extracted with ethyl acetate (2 X 250 mL). The combined organic layers were dried over anhydrous sodium sulphate and concentrated under high vacuum to obtain the crude material. The material was purified by flash column chromatography on silica gel using 1% ethyl acetate in hexane as eluent to get ethyl 4- bromoisothiazole-5-carboxylate (Qty: 2.4 g, 67%). LCMS (m / z): 234.1 [M-l]'.

[0292] Step 2. To a stirred solution of 4-bromoisothiazole-5-carboxylate (2.1 g, 8.9 mmol. 1 eq.) and ethynyl -trimethyl silane (1.74 g, 17.8 mmol, 2 eq.) in tetrahydrofuran (42 mL, 20 vol) was added triethylamine (31.5 g, 15 vol.). The reaction mixture was purged with nitrogen gas for 15 minutes and copper(I) bromide (0.09 g, 0.6 mmol, 0.07 eq.), lithium bromide (0.02 g, 0.2 mmol, 0.03 eq.), tetrakis(triphenylphosphine)palladium(0) (0.1 g, 0.09 mmol, 0.01 eq.), triphenyl phosphine (TPP) (0.093 g, 0.35 mmol. 0.04 eq.) were added in sequence at room temperature. The reaction mixture was further allowed to stir at 80 °C for 2 h. The completion of reaction was monitored by TLC using 5% ethyl acetate in hexane and LCMS analysis. The reaction mixture was quenched with water (250 mL) and extracted with ethyl acetate (2 X 125 mL). The combined organic layers were dried over sodium sulphate and concentrated under high vacuum to obtain the crude residue. The material was purified by flash column chromatography on silica gel using 1% ethyl acetate in hexane as eluent to get ethyl 4-((trimethylsilyl)ethynyl)isothiazole- 5-carboxylate (Qty: 2 g, 89%). LCMS (m / z): 254.1 [M+H]1.

[0293] Step 3. A solution of ethyl 4-((trimethylsilyl)ethynyl)isothiazole-5-carboxylate (2.0 g, 7.9 mmol, 1.0 eq.) in 7 M ammonia in methanol (20 mL, 10 vol) was allowed to stir at 75 °C for 4 h. The completion of reaction was monitored by TLC using 20% ethyl acetate in hexane and LCMS analysis. The reaction mixture was concentrated under reduced pressure to obtain the crude material. Tire material was triturated with hexane (2 x 50 mL) to get 4-ethynylisothiazole-5-carboxamide (Qty: 1 g, 83%). LCMS (m / z): 151.2 [MJ‘.

[0294] Step 4. To a stirred solution of 4-ethynylisothiazole-5-carboxamide (0.5 g, 3 mmol, 1 .0 eq.) in methanol (10 mL, 20 vol) was added a solution of dimethylamine (2.0 M in tetrahydrofuran) (10 mL, 20 vol). The reaction mixture was allowed to stir at 75 °C for 4 h. Tire completion of reaction was monitored by TLC using 30% ethyl acetate in hexane and LCMS analysis. Tire reaction mixture was concentrated under reduced pressure to obtain the crude material. The material was purified by flash column94BUSINESS.33535339.1chromatography on silica gel using 28% ethyl acetate in hexane as eluent to get isothiazolo[5,4-c]pyridin- 7(6H)-one (Qty: 0.3 g, 60%). LCMS (m / z): 153.0 [M+H]+.

[0295] Step 5. To a stirred solution of isothiazolo[5,4-c]pyridin-7(6H)-onc (0.2 g, 1 mmol, 1.0 cq.) in acetonitrile (4 mL, 20 vol) was added phosphorus oxybromide (0.565 g, 1.97 mmol, 1.5 eq.) at 0°C. Hie reaction mixture was allowed to stir at 80 °C for 2 h. The completion of reaction was monitored by TLC using 10% ethyl acetate in hexane and LCMS analysis. The reaction mixture was quenched with cold water (100 mL) and extracted with ethyl acetate (2 X 25 mL). The combined organic layers were dried over sodium sulphate and concentrated under reduced pressure to obtain the crude residue. The material was purified by flash column chromatography on silica gel using 7% ethyl acetate in hexane as eluent to get 7- bromoisothiazolo[5,4-c]pyridine (Qty: 0.16 g, 57%). LCMS (m / z): 216.9 [M+H]+.

[0296] Step 6. To a stirred solution of 7-bromoisothiazolo[5,4-c]pyridine (0.07 g, 0.3 mmol, 1.0 eq.) and the first eluting fraction of the chirally-separated tert-butyl (4-(4,4,5,5-tetramethyl-l ,3,2-dioxaborolan- 2-yl)cyclohex-3-en-l-yl)carbamate (see example method 2, 0.157 g, 0.488 mmol, 1.5 eq.) in 1, 4 dioxane (1.4 mL, 20 vol) and water (0.07 mL, 1 vol) was added tri-potassium phosphate (K3PO4) (0.207 g, 0.976 mmol, 3 eq.). The reaction mixture was purged with nitrogen gas for 10 minutes and Pd(dppf)CL.DCM complex (0.03 g, 0.03 mmol, 0. 1 eq.) was added at room temperature. The reaction mixture was allowed to stir at 100 °C for 2 h. The completion of reaction was monitored by TLC using 30% ethyl acetate in hexane and LCMS analysis. The reaction mixture was quenched with water (25 mL) and extracted with ethyl acetate (2 X 20 mL). The combined organic layers were dried over sodium sulphate and concentrated under high vacuum to obtain the crude material. The material was purified by flash column chromatography on silica gel using 22% ethyl acetate in hexane as eluent to afford tert-butyl (4-(isothiazolo[5,4-c]pyridin-7- yl)cyclohex-3-en-l-yl)carbamate (Qty: 0.09 g, 83%). LCMS (m / z): 332.1 [M+H]1.

[0297] Step 7. To a stirred solution of 7-bromoisothiazolo[5,4-c]pyridine (0.07 g, 0.3 mmol, 1.0 eq.) and the second eluting fraction of the chirally-separated tert-butyl (4-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)cyclohex-3-en-l-yl)carbamate (0.157 g, 0.488 mmol, 1.5 eq.) in 1, 4 dioxane (1.4 mL, 20 vol) and water (0.07 mL, 1 vol) was added tri-potassium phosphate (K3PO4) (0.207 g, 0.976 mmol, 3 eq.). The reaction mixture was purged with nitrogen gas for 10 minutes and Pd(dppf)C12.DCM complex (0.03 g, 0.03 mmol. 0.1 eq.) was added at room temperature. The reaction mixture was allowed to stir at 100 °C for 2 h. The completion of the reaction was monitored by TLC using 30% ethyl acetate in hexane and LCMS analysis. The reaction mixture was quenched with water (25 mL) and extracted with ethyl acetate (2 X 20 mL). The combined organic layers were dried over sodium sulphate and concentrated under high vacuum to obtain the crude material. Tire material was purified by flash column chromatography on silica gel using 22% ethyl acetate in hexane as eluent to afford tert-butyl (4-(isothiazolo[5,4-c]pyridin-7- yl)cyclohex-3-en-l-yl)carbamate (Qty: 0.09 g, 83%). LCMS (m / z): 332.1 [M+H]+.95BUSINESS.33535339.1

[0298] Step 8. To a stirred solution of tert-butyl (4-(isothiazolo[5,4-c]pyridin-7-yl)cyclohex-3-en-l - yl)carbamate prepared from the first eluting fraction as in step 6 (0.08 g, 0.2 mmol, 1.0 eq.) in dichloromcthanc (1.6 mL, 20 vol) was added 4M hydrochloric acid in 1, 4 dioxane (0.4 mL, 5 vol) at 0 °C. The reaction mixture was allowed to stir at room temperature for 16 h. The completion of reaction was monitored by TLC using 10% methanol in dichloromethane and LCMS analysis. The reaction mixture was concentrated under reduce pressure to obtain the crude material. The material was triturated with diethyl ether (4 x 20 mL) to afford 4-(isothiazolo[5,4-c]pyridin-7-yl)cyclohex-3-en-l-amine hydrochloride (1-42) (Qty:0.058 g, 90%) as off white solid. LCMS (m / z): 232.1 [M+H]+. Analytical chiral HPLC: Column CHIRALPAK IG (250x4.6mm, 5 pm), Solvent: 0. 1% methanolic ammonia in IPA:MeOH (50:50), Injection volume: 25 pL, Retention time: 6.19 min. Wavelength: 325 nm; 1H NMR (400 MHz, DMSO): 8 9.33 (s, 1H). 8.64 (d, J = 5.0 Hz, 1H), 8.23 (s. 3H), 8.11 (d, J = 5.5 Hz, 1H), 6.61 (s, 1H). 3.43 (bs, 1H), 2.98 (d, J = 17.0 Hz, 1H), 2.80-2.76 (m, 2H), 2.50-2.49 (m, 1H), 2.19-2.16 (m, 1H), 1.83-1.79 (m, 1H).

[0299] Step 9. To a stirred solution of tert-butyl (4-(isothiazolo[5,4-c]pyridin-7-yl)cyclohex-3-en-l- yl)carbamate prepared from the second eluting fraction as in step 7 (0.08 g, 0.2 mmol, 1.0 eq.) in dichloromethane (1.6 mL, 20 vol) was added 4M hydrochloric acid in 1, 4 dioxane (0.4 mL, 5 vol) at 0 °C. The reaction mixture was allowed to stir at room temperature for 16 h. The completion of reaction was monitored by TLC using 10% methanol in dichloromethane and LCMS analysis. The reaction mixture was concentrated under reduce pressure to obtain the crude material. The material was triturated with diethyl ether (4 x 20 mL) to afford 4-(isothiazolo[5,4-c]pyridin-7-yl)cyclohex-3-en-l-amine hydrochloride (1-43) (Qty:0.059 g, 91%) as off white solid. LCMS (m / z): 232.1 [M+H]+. Analytical chiral HPLC: Column CHIRALPAK IG (250x4.6mm, 5 pm), Solvent: 0.1% methanolic ammonia in MeGH:IPA(50:50), Injection volume: 25 pL, Retention time: 6.36 min. Wavelength: 325 nm; 1H NMR (400 MHz, DMSO): 8 9.33 (s, 1H), 8.62 (d, J = 5.0 Hz, 1H), 8.23 (s, 3H), 8.11 (d, J = 5.5 Hz, 1H), 6.61 (s, 1H), 3.43 (bs, 1H), 2.98 (d, J = 17.20 Hz, 1H), 2.80-2.76 (m, 2H), 2.50-2.49 (m, 1H), 2.19-2.16 (m, 1H), 1.86-1.76 (m, 1H).96BUSINESS.33535339.1

[0300] Example 7 (T-44)NaNO AcOH

[0301] Step 1. To a stirred solution of 3-bromo-4-methylbenzene-l,2-diamine (0.20 g, 0.99 mmol, 1 eq.) in acetic acid (2.0 mL, 10 vol) was added solution of sodium nitrite (0.11 g, 1.6 mmol, 1.64 eq.) in water (1.4 mL, 7 vol) at 0 °C temperature. Tire reaction mixture was allowed to stir at room temperature for 1 li. Hie completion of reaction was monitored by TLC using 50% ethyl acetate in hexane and LCMS analysis. The reaction mixture quenched with water (30 mL) and extracted with ethyl acetate (2 X 30 mL). The combined organic layers were dried over sodium sulphate and concentrated under a high vacuum to obtain the crude material. The material was concentrated under reduced pressure. The isolated material was triturated with diethyl ether (2 x 5 mL) and dried in vacuo to afford 4-bromo-5-methyl-lH- benzo[d][l,2,3]triazole (Qty: 0.15 g, 71%). LCMS (m / z): 212.1 [M+H]+.

[0302] Step 2. To a stirred solution of 4-bromo-5-methyl-lH-benzo[d][l,2,3]triazole (0.15 g, 0.71 mmol. 1 eq.) and 3, 4 dihydro-2-pyran (0.15 g. 0.71 mmol. 1 eq.) in dichloromethane (1.0 mL, 10 vol) was added p-toluene sulfonic acid (0.10 g, 0.59 mmol, 1.0 eq.) at room temperature. The reaction mixture was allowed to stir at 50 °C for 1 h. The completion of reaction was monitored by TLC using 30% ethyl acetate in hexane and LCMS analysis. The reaction mixture was quenched with water (50 mL) and extracted with ethyl acetate (2 X 50 mL). Hie combined organic layers were dried over sodium sulphate and concentrated under a high vacuum to obtain the crude residue. The material was purified by flash column chromatography on silica gel using 10 % ethyl acetate in hexane as eluent to get 4-bromo-5 -methyl- 1- (tetrahydro-2H-pyran-2-yl)-lH-benzo[d][l,2,3]triazole (Qty: 0.13 g, 62%). 1H NMR (400 MHz, DMSO):97BUSINESS.33535339.1410095-003WO (221371)5 7.84 (d, J = 8.5 Hz, 1H), 7.56 (d, J = 8.5 Hz, 1H), 6.17-6.14 (dd, J = 9.0, 3.0, 1H), 3.89-3.38 (m, 2H), 2.52-2.50 (m, 3H), 2.46-2.42 (m, 2H), 2.14-2.11 (m, 2H), 1.79-1.45 (m, 2H).

[0303] Step 3. To a stirred solution of 4-bromo-5-mcthyl-l-(tctrahydro-2H-pyran-2-yl)-lH- benzo[d][l,2,3]triazole (0.09 g, 0.3 mmol. 1 eq.) and tert-butyl 5-(4,4,5.5-tetramethyl-l,3,2-dioxaborolan- 2-yl)-3,6-dihydropyridine-l(2H)-carboxylate (0.10 g, 0.30 mmol, 1 eq.) in 1,4-dioxane (0.9 mL, 10 vol) and water (0.1 mL, 1 vol) was added tri potassium phosphate (K3PO4) (0.19 g, 0.91 mmol, 3.0 eq.). The reaction mixture was purged with nitrogen gas for 15 minutes and Pd(dppf)C12.DCM complex (0.02 g, 0.03 mmol, 0.1 eq.) was added at room temperature. The reaction mixture was allowed to stir at 100°C for 3h. Tire completion of reaction was monitored by TLC using 30% ethyl acetate in hexane and LCMS analysis. The reaction mixture was quenched with water (25 mL) and extracted with ethyl acetate (2 X 25 mL). Hie combined organic layers were dried over sodium sulphate and concentrated under a high vacuum to obtain the crude residue. The material was purified by manual column chromatography on silica gel using 28% ethyl acetate in hexane as eluent to get tert-butyl (4-(5-methyl-l-(tetrahydro-2H-pyran-2-yl)-lH- benzo[d][l,2,3]triazol-4-yl)cyclohex-3-en-l-yl)carbamate (Qty: 0.1 g, 80%). LCMS (m / z): 413.4 [M+H]+.

[0304] Step 4. To a stirred solution of tert-butyl (4-(5-methyl-l-(tetrahydro-2H-pyran-2-yl)-lH- benzo[d][l,2,3]triazol-4-yl)cyclohex-3-en-l-yl)carbamate (0.10 g. 0.24 mmol, 1.0 eq.) in dichloromethane (1.0 mL, 10 vol) was added 4M hydrochloric acid in 1. 4 dioxane (0.5 mL, 5 vol) at 0 °C. The resulting mixture stirred at room temperature for 3 h. The completion of reaction was monitored by TLC using 5% methanol in dichloromethane and LCMS analysis. After completion of reaction, the reaction mixture was concentrated under reduce pressure. The isolated material was triturated with diethyl ether (2 x 5 mL) and dried in vacuo to afford racemic 4-(5-methyl-lH-benzo[d][l,2,3]triazol-4-yl)cyclohex-3-en-l-amine hydrochloride (1-44) (0.06g. 94%). LCMS (m / z): 229.2 [M+H]1; 1H NMR (4OO MHz, DMSO): 8 8.18 (s, 3H), 7.74 (d, J = 8.5 Hz, 1H), 7.27 (d, J = 8.5 Hz, 1H), 5.63 (s, 1H), 3.49 (s, 1H), 2.61-2.55 (m, 1H), 2.50- 2.45 (m, 1H), 2.36 (s, 3H), 2.33-2.27 (m, 2H), 2.13-2.10 (m, 1H), 1.91-1.87 (m, 1H).

[0305] Additional Exemplary Compounds Prepared via Example 7 Methods98BUSINESS.33535339.1

[0306] Example 8 (T-46)Step 1

[0307] Step 1. To a stirred solution of (R)-octahydropyrrolo[ l .2-a|pyrazinc (0.1 g, 0.8 mmol, 1.0 eq.) in tetrahydrofuran ( 1 mL, 10 vol) was added triethylamine (TEA) (0.12 g. 1.2 mmol. 1.5 eq.) and 4- chlorothieno[3,2-d]pyrimidine. The reaction mixture was allowed to stir at 80 °C for 1 h. The completion of reaction was monitored by TLC using 80% ethyl acetate in hexane and LCMS analysis. The reaction mixture was quenched with water (50 mL) and extracted with ethyl acetate (2 X 50 mL). Tire combined organic layers were dried over sodium sulphate and concentrated under high vacuum to obtain the crude residue. The material was purified by flash column chromatography on silica gel using 3% methanol in dichloromethane as eluent to get (R)-4-(hexahydropyrrolo[1.2-a]pyrazin-2(lH)-yl)thieno[3,2-d]pyrimidine (1-46) (Qty: 0.09 g, 44%) as light brown sticky solid. LCMS (m / z): 261 .2 [M+H]+; Analytical chiral HPLC: Column CHIRALPAK IG-3 (100x3mm, 3 pm). Solvent: 0.1% methanolic ammonia in MeOH:ACN (50:50), Injection volume: 2 pL, Retention time: 2.159 min, Wavelength: 255 nm; 1H NMR (400 MHz, DMSO): 8 8.48 (s, 1H), 8.20 (d. J = 5.5 Hz, 1H), 7.43 (d, J = 5.5 Hz, 1H), 4.83 (dt, J = 12.5, 2.5 Hz, 1H), 4.65 (dd, J = 12.0, 1.5 Hz, 1H), 3.25 (td, J = 12.0, 9.0, Hz, 1H), 3.09-3.04 (m, 1H), 3.O1 (td, J = 8.5, 6.0 Hz, 1H), 2.92-2.86 (m, 1H), 2.18-2.08 (m, 1H), 2.07 (q, J = 9.0 Hz, 1H), 2.00-1.97 (m, 1H), 1.84-1.83 (m, 1H), 1.73-1.66 (m, 2H), 1.41-1.37 (m, 1H).

[0308] Additional Exemplary Compounds Prepared via Example 8 Methods99BUSINESS.33535339.1

[0309] Example 9 (T-50 and 1-51)1 ,4-Dioxane:Water(9:1),100°C, 1 h

[0310] Step 1. To a stirred solution of 3-bromo-4-chloropyridine (60.0 g, 311 mmol) in tetrahydrofuran (900 mL, 15 vol) was added a solution of LDA (2.0 M in tetrahydrofiiran) (155 rnL. 311 mmol) at -78 °C. The reaction mixture was allowed to stir at -78 °C for 1 h and dimethylformamide (22.8 g, 311 mmol) was added. The reaction mixture was allowed to stir at room temperature for 3 h. The progress of the reaction was monitored by TLC using 10 % ethyl acetate in hexane and LCMS analysis. After100BUSINESS.33535339.1completion of the reaction, the reaction mixture was quenched with saturated ammonium chloride solution (2000 mL) and extracted with ethyl acetate (3 X 1000 mL). The combined organic layers were dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure to obtain the crude material. Tire crude material was purified by flash column chromatography on silica gel using 3% ethyl acetate in hexane as an eluent to afford 5-bromo-4-chloronicotinaldehyde (35 g, 51%) as a light-yellow solid. 'H NMR (400 MHz, DMSO-tL) 5 10.27 (s. 1H), 9.09 (s, 1H). 8.89 (s, 1H).

[0311] Step 2. To a stirred solution of 5-bromo-4-chloronicotinaldehyde (35.0 g, 158 mmol) in acetonitrile (350 mL, 10 vol) were added triethylamine (44.3 mL, 316 mmol) and ethyl 2-mercaptoacetate. Tire reaction mixture was allowed to stir at 45 °C for 12 h. The progress of the reaction was monitored by TLC using 20 % ethyl acetate in hexane and LCMS analysis. After completion of the reaction, the reaction mixture was quenched with water (1000 mL) and extracted with ethyl acetate (2 X 500 mL). Tire combined organic layers were dried over anhydrous sodium sulphate and concentrated under reduced pressure to afford the crude material. The crude material was purified by flash column chromatography on silica gel using 10% ethyl acetate in hexane as an eluent to afford ethyl 7-bromothieno[3,2-c]pyridine-2-carboxylate (20 g, yield: 44%) as a white solid. LCMS (m / z): 286.1 [M+H]+.

[0312] Step 3. To a stirred solution of ethyl 7-bromothieno[3.2-c]pyridine-2-carboxylate (10.0 g, 35.0 mmol) in methanol (100 mL, 10 vol) was added sodium hydroxide (7.0 g, 180 mmol) in water (50 mL, 5 vol) at 0 °C. The reaction mixture was further stirred at room temperature for 1 h. The progress of the reaction was monitored by TLC (40 % ethyl acetate in hexane) and LCMS analysis. A second reaction was carried out in parallel, also using 10 g ethyl 7-bromothicno [3 ,2-c]pyridinc-2 -carboxylate. After completion of both parallel reactions, the two mixtures were combined and concentrated under high vacuum. Hie crude material was quenched with a 1 M solution of hydrochloric acid to adjust the pH to ~8. The precipitated solid was filtered and dried to afford 7-bromothieno[3,2-c]pyridine-2 -carboxylic acid as off white solid (16 g, 89 %). LCMS (m / z): 257.9 [M+H]+.

[0313] Step 4. To a stirred solution of 7-bromothieno[3,2-c]pyridine-2-carboxylic acid (4.0 g, 16 mmol) in tert-butanol were added N, A-diisopropylethylamine (2.93 mL, 17.0 mmol) and diphenylphosphorylazide (4.9 g, 18.1 mmol). The reaction mixture was allowed to stir at 100 °C for 8 h. The progress of the reaction was monitored by TLC using 40 % ethyl acetate in hexane and LCMS analysis. Three additional reactions, each also using 4.0 g 7-bromothieno[3,2-c]pyridine-2-carboxylic acid, were carried out in parallel. After completion of the parallel reactions, the mixtures were combined and concentrated under reduced pressure. The obtained crude material was purified by flash column chromatography on silica gel using 25 % ethyl acetate in hexane as eluent to get tert-butyl (7- bromothieno[3,2-c]pyridin-2-yl)carbamate (4.5 g, 22 %) as light-yellow solid. LCMS (m / z): 329.1 [M+H]+.101BUSINESS.33535339.1

[0314] Step 5. To a stirred solution of tert-butyl (7-bromothieno[3,2-c]pyridin-2-yl)carbamate (0.5 g, 2 mmol) in tetrahydrofuran (10 mL, 10 vol) was added A-chlorosuccinimide (NCS) (1.01 g, 7.59 mmol). Tire reaction mixture was allowed to stir at room temperature for 4 h. The progress of the reaction was monitored by TLC using 40 % ethyl acetate in hexane and LCMS analysis. After completion of the reaction, the reaction mixture was quenched with a saturated solution of sodium thiosulphate (60 mL) and extracted with ethyl acetate (3 X 40 mL). The combined organic layers were dried over anhydrous sodium sulphate and concentrated under high vacuum to afford the crude residue. The crude material was purified by flash column chromatography on silica gel using 15% ethyl acetate in hexane as eluent to afford tert-butyl (7- bromo-3-chlorothieno[3,2-c]pyridin-2-yl)carbamate (0.41 g, 74 %) as a light-orange solid. LCMS (m / z): 362.9 [M+H]+.

[0315] Step 6. A solution of tert-butyl (7-bromo-3-chlorothieno[3.2-c]pyridin-2-yl)carbamate (0.4 g. 1 mmol, 1 .0 eq.) in trifluoroacetic acid (4 mL, 10 vol) was allowed to stir at room temperature for 30 min. The progress of the reaction was monitored by TLC using 20 % ethyl acetate in hexane and LCMS analysis. Upon completion of the reaction, the reaction mixture was quenched with saturated aqueous solution of sodium bicarbonate (100 mL) and extracted with ethyl acetate (2 X 25 mL). The combined organic layers were dried over sodium sulphate, fdtered and concentrated under high vacuum to afford the crude material. The crude material was purified by flash column chromatography on silica gel using 15 % ethyl acetate in hexane as eluent to afford 7-bromo-3-chlorothieno[3,2-c]pyridin-2-amine (0.21 g, 72%) as orange solid. LCMS (m / z): 262.9 [M+H]+.

[0316] Step 7. A solution of tert-butyl nitrite (1 mL, 5 vol) in dimethylformamide (2 mL. 10 vol) was heated at 60 °C. To the above reaction mixture, a solution of 7-bromo-3-chlorothieno[3.2-c]pyridin-2 -amine (0.2 g. 0.8 mmol) in dimethylformamide (0.5 mL) was added and the mixture was allowed to stir at 60 °C for 1 h. The progress of the reaction was monitored by TLC using 20 % ethyl acetate in hexane and LCMS analysis. After completion of the reaction, the reaction mixture was quenched with water (20 mL) and extracted with ethyl acetate (2 X 15 mL). The combined organic layers were dried over sodium sulphate and concentrated under high vacuum to afford the crude material. The crude material was purified by flash column chromatography on silica gel using 3 % ethyl acetate in hexane as eluent to afford 7-bromo-3- chlorothieno[3,2-c]pyridine (0.07 g. 37%) as a off white solid. LCMS (m / z): 247.9 [M+H]+.

[0317] Step 8. To a stirred solution of 7-bromo-3-chlorothieno[3,2-c]pyridine (0.03 g, 0.1 mmol) and tert-butyl (4-(4,4, 5 ,5 -tetramethyl- 1 ,3 ,2-dioxaborolan-2-yl)cyclohex-3 -en- 1 -yl)carbamate (eluting fraction 1 from example method 2, 0.078 g, 0.24 mmol) in 1,4-dioxane (0.6 mL, 20 vol) and water (0.06 mL, 2 vol) was added tri-potassium phosphate (K3PO4) (0.076 g. 0.36 mmol). The reaction mixture was purged with nitrogen gas for 10 minutes and Pd(dppf)CL.DCM complex (0.009 g, 0.01 mmol) was added at room temperature. The reaction mixture was allowed to stir at 100 °C for 4 h. The completion ofthe reaction was102BUSINESS.33535339.1410095-003WQ (221371) monitored by TLC using 30 % ethyl acetate in hexane and LCMS analysis. After completion of the reaction, the reaction mixture quenched with water (20 mL) and extracted with ethyl acetate (2 X 10 mL). The combined organic layers were dried over sodium sulphate and concentrated under reduced pressure. The obtained crude material was purified by flash column chromatography on silica gel using 20 % ethyl acetate in hexane as eluent to afford tert-butyl (4-(3-chlorothieno[3,2-c]pyridin-7-yl)cyclohex-3-en-l-yl)carbamate (from eluting fraction 1 in example 2, 0.03 g, 68%). LCMS (m / z): 365.1 [M+H]+.

[0318] Step 9. Tire same procedure as in step 8 was applied, but using eluting fraction 2 (instead of eluting fraction 1) of tert-butyl (4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)cyclohex-3-en-l- yl)carbamate from example method 2 to afford tert-butyl (4-(3-chlorothieno[3,2-c]pyridin-7-yl)cyclohex- 3-en-l-yl)carbamate (0.03 g, 68 %). LCMS (m / z): 365.1 [M+H]+.

[0319] Step 10. To a stirred solution of tert-butyl (4-(3-chlorothieno[3,2-c]pyridin-7-yl)cyclohex-3- en-l-yl)carbamate (prepared from eluting fraction 1 as in step 8, 0.025 g, 0.068 mmol) in dichloromethane (0.5 mL, 20 vol) was added 4 M hydrochloric acid in 1,4-dioxane (0.125 mL, 5 vol) at 0 °C. Tire reaction mixture was allowed to stir at room temperature for 4 h. The progress of the reaction was monitored by TLC using 5 % methanol in dichloromethane and LCMS analysis. After completion of reaction, the reaction mixture was concentrated under reduced pressure. Tire crude material was triturated with diethyl ether (4 x 10 mL) and dried well under vacuum to afford 4-(3-chlorothieno[3.2-c]pyridin-7-yl)cyclohex-3-en- 1 -amine hydrochloride (1-50, 11.6 mg, 56%) as an off-white solid. LCMS (m / z): 265.1 [M+H]+; Analytical chiral HPLC: Column Chiralpak IG-3 (100 mm x 3 mm, 3 pm); Mobile Phase: 0.1% methanolic NIL in McOH:ACN (50:50); Wavelength: 225 nm; RT 3. 141 mm: 'HNMR (400 MHz, DMSO L) 59.15 (s, 1H),8.62 (s, 1H), 8.28 (s, 3H), 8.26 (s, 1H), 6.31 (s, 1H), 3.41 (s, 1H), 2.69-2.49 (m, 3H), 2.41-2.23 (m, 1H), 2.20-2.10 (m, 1H), 1.85-1.84 (m, 1H).

[0320] Step 11. Tire same procedure as in step 10 was applied, instead using tert-butyl (4-(3- chlorothieno[3,2-c]pyridin-7-yl)cyclohex-3-en-l-yl)carbamate prepared from eluting fraction 2 (as in step 9, 0.025 g, 0.068 mmol) to afford 4-(3-chlorothieno[3,2-c]pyridin-7-yl)cyclohex-3-en-l-amine hydrochloride (1-51. 10.2 mg, 50%) as an off-white solid. LCMS (m / z): 265.1 [M+H]+; Analytical chiral HPLC: Column Chiralpak IG-3 (100 mm x 3 mm, 3 pm); Mobile Phase: 0.1% methanolic NIL in MeOH:ACN (50:50); Wavelength: 225 nm; RT 3.447 mm; ’H NMR (400 MHz. DMSO-t / e) 59.16 (s. 1H),8.63 (s, 1H), 8.31 (s, 3H), 8.28 (s, 1H), 6.32 (s, 1H), 3.40 (s, 1H), 2.69-2.48 (m, 3H), 2.39-2.23 (m, 1H), 2.20-2.10 (m, 1H), 1.87-1.82 (m, 1H).103BUSINESS.33535339.1410095-003WQ (221371)

[0321] Example 10 (1-53 and 1-54)100°C, 1 h

[0322] Step 1. To a stirred solution of thieno[2,3-c]pyridin-7(6H)-one (1.00 g, 6.61 mmol) in dimethylacetamide (5.00 mL, 5 vol) was added Selectfluor (2.80 g, 7.93 mmol) portion-wise at room temperature. Hie reaction mixture was allowed to stir under microwave irradiation at 150 °C for 20 minutes. The progress of the reaction was monitored by TLC using 100 % ethyl acetate and LCMS analysis. After completion of the reaction, the reaction mixture was concentrated under reduced pressure. The obtained crude material was purified by flash column chromatography on silica gel using 30% ethyl acetate in hexane as eluent to afford 4-fluorothieno[2,3-c]pyridin-7(6H)-one (0.40 g, 36 %) as a light-pink solid. LCMS (m / z): 170.0 [M+H]+.

[0323] Step 2. To a stirred solution of 4-fluorothieno[2,3-c]pyridin-7(6H)-one (0.40 g, 2.4 mmol) in acetonitrile (4.00 mL, 10 vol) was added phosphoryl tri -bromide (1.00 g. 3.55 mmol) at 0 °C under nitrogen atmosphere. The reaction mixture was allowed to stir at 80 °C for 16 h. The progress of the reaction was104BUSINESS.33535339.1410095-003WQ (221371) monitored by TLC using 60 % ethyl acetate in hexane and LCMS analysis. After completion of the reaction, the reaction mixture was concentrated under reduced pressure. The obtained crude material was purified by flash column chromatography on silica gel using 100% hexane as eluent to afford 7-bromo-4- fluorothieno[2,3-c]pyridine (0.30 g, 55 %) as light-orange solid. LCMS (m / z): 232.0 [M+H]+.

[0324] Step 3. To a stirred solution of 7-bromo-4-fluorothieno[2,3-c]pyridine (0.13 g. 0.56 mmol) and tert-butyl (4-(4,4,5,5-tetramethyl-L3,2-dioxaborolan-2-yl)cyclohex-3-en-l-yl)carbamate (eluting fraction 1 from example method 2, 0.22 g, 0.67 mmol) in 1,4-dioxane (1.2 mL, 9 vol) and water (0.13 mL, 1 vol) was added tri-potassium phosphate (K3PO4) (0.36 g, 1.7 mmol). The reaction mixture was purged with nitrogen gas for 15 minutes and Pd(dppf)C12.DCM complex (0.046 g, 0.056 mmol) was added at room temperature under a nitrogen atmosphere. Tire reaction mixture was allowed to stir at 100 °C for 1 h. Hie progress of the reaction was monitored by TLC using 20 % ethyl acetate in hexane and LCMS analysis. After completion of the reaction, the reaction mixture was quenched with water (30 mL) and extracted with 10 % methanol in dichloromethane (3 X 20 mL). The combined organic layers were dried over anhydrous sodium sulphate and concentrated under high vacuum. The obtained crude material was purified by flash column chromatography on silica gel using 4 % ethyl acetate in hexane as eluent to afford tert-butyl (4-(4- fluorothieno[2,3-c]pyridin-7-yl)cyclohex-3-en-l-yl)carbamate (prepared from eluting fraction 1. 0.08 g, 41 %) as light-orange solid. LCMS (m / z): 349.2 [M+H]+.

[0325] Step 4. The same procedure as in step 4 was applied, but using eluting fraction 2 (instead of eluting fraction 1) of tert-butyl (4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)cyclohex-3-en-l- yl)carbamatc from example method 2 to afford tert-butyl (4-(4-fluorotliicno[2,3-c]pyridin-7-yl)cyclohcx- 3-en-l-yl)carbamate (from eluting fraction 2, 0.06 g, 40 %) as of white solid. LCMS (m / z): 349.2 [M+H]+.

[0326] Step 5. To a stirred solution of tert-butyl (4-(4-fluorothieno[2.3-c]pyridin-7-yl)cyclohex-3-en- l-yl)carbamate prepared from eluting fraction 1 as in step 3 (0.06 g, 0.2 mmol, 1 .0 eq.) in dichloromethane (1.2 mL, 20 vol) was added 4 M hydrochloric acid in 1,4-dioxane (0.3 mL, 5 vol) at 0 °C under an inert atmosphere of nitrogen gas. The resulting mixture stirred at room temperature for 1 h. The progress of the reaction was monitored by TLC using 10 % methanol in dichloromethane. After completion of reaction, the reaction mixture was concentrated under reduced pressure. The obtained residue was resuspended in DCM (10 mL), then the solvent was removed by distillation in order to remove trapped volatile impurities. This was repeated with a second portion of DCM (10 mL) to afford solid material which was further triturated with acetonitrile (2 X 5 mL) and diethyl ether (1 X 4 mL) followed by drying under vacuum to afford 4-(4- fluorothicno[2,3-c]pyridin-7-yl)cyclohcx-3-cn-l-aminc hydrochloride (1-53, 0.053 g) as an off-white solid. LCMS (m / z): 249.1 | M+H| : Analytical chiral HPLC: Column Chiralpak IC-3 (100 mm x 3 mm, 3 pm); Mobile Phase: 0. 1% methanolic NH3 in IPA:ACN (50:50); Wavelength: 210 nm; RT 2.426 min; ’H NMR (400 MHz, DMSO-tL) 5 8.48 (d, J= 1.5 Hz, 1H), 8.31 (bs, 3H), 8.26 (d, J = 5.5 Hz, 1H), 7.68 (d, J= 5.5105BUSINESS.33535339.1Hz, 1H), 6.58-6.56 (m, 1H), 3.45-3.35 (m, 1H), 2.89-2.85 (m, 1H), 2.80-2.55 (m, 2H), 2.45-2.30 (m, 1H), 2.20-2.10 (m, 1H), 1.82-1.76 (m, 1H).

[0327] Step 6. The same procedure as in step 5 was applied, but using tert-butyl (4-(4- fluorothieno[2,3-c]pyridin-7-yl)cyclohex-3-en-l-yl)carbamate prepared from eluting fraction 2 (as in step 4, 0.06 g, 0.2 mmol) to afford 4-(4-fluorothieno[2,3-c]pyridin-7-yl)cyclohex-3-en-l-amine hydrochloride (1-54, 0.049 g) as an off-white solid. LCMS (m / z): 249.1 [M+H]+; Analytical chiral HPLC: Column Chiralpak IC-3 (100 mm x 3 mm, 3 pm); Mobile Phase: 0.1% methanolic NH3 in IPA:ACN (50:50); Wavelength: 210 nm; RT 2.475 min; 'HNMR (400 MHz, DMSO / <) 5 8.47 (d, J= 1.5 Hz, 1H), 8.31 (bs, 3H), 8.26 (d, J = 5.5 Hz, 1H). 7.68 (d, J = 5.5 Hz, 1H), 6.60-6.55 (m, 1H), 3.45-3.35 (m, 1H), 2.95-2.85 (m, 1H). 2.75-2.60 (m, 2H), 2.44-2.37 (m, 1H), 2.20-2.15 (m, 1H), 1.81-1.77 (m, 1H).

[0328] Example 11 (1-56 and 1-57)

[0329] Step 1. To a stirred solution of tert-butyl (3 -hydroxy cyclobutyl)carbamate (1.00 g, 5.34 mmol) in tetrahydrofiiran (20 mb, 20 vol) were added carbon tetrabromide (3.50 g, 10.7 mmol) and triphenylphosphine (2.80 g, 10.7 mmol) portion-wise at room temperature. The reaction mixture was allowed to stir at room temperature for 20 h. The completion of the reaction was monitored by TLC using 10% ethyl acetate in hexane (KMnCU staining reagent). After completion of the reaction, the reaction mixture was poured into water (125 mL) and extracted with ethyl acetate (2 X 75 mL). The combined organic layers were dried over anhydrous Na SCL and concentrated under reduced pressure to afford the crude material. Tire crude residue was purified by flash column chromatography on silica gel using 8% ethyl acetate in hexane as eluent to afford tert-butyl (3-bromocyclobutyl)carbamate (0.40 g, 30%) as a white106BUSINESS.33535339.1solid. 'H NMR (400 MHz, DMSO-tL) 5 7.33 (m, 1H), 4.59-4.55 (m, 1H), 4.36-4.30 (m, 1H), 2.61-2.47 (m, 4H), 1.36 (s, 9H).

[0330] Step 2. Preparation of Solution A. A solution of 7-bromothicno[2,3-c]pyridinc (0.5 g, 2 mmol), tert-butyl (3-bromocyclobutyl)carbamate (1.16 g, 4.67 mmol), tris(trimethylsilyl)silane (0.58 g, 2.3 mmol), [4.4'-Bis(l,l-dimethylethyl)-2,2'-bipyridine-Nl.Nl']bis[3,5-difluoro-2-[5-(trifluoromethyl)-2-pyridinyl- N]phenyl-C] Iridium (III) hexafluorophosphate (0.052 g, 0.046 mmol), and sodium carbonate (0.49 g, 4.7 mmol) in dimethoxy ethane (DME) (10 mL, 20 vol) was allowed to stirred at room temperature under argon atmosphere for 10 minutes.

[0331] Preparation of pre-catalyst solution. In a separate vial, a solution of nickel(II)chloride ethylene glycol dimethyl ether complex (0.01 g, 0.0467 mmol) and 4,4’-Di-tert-butyl-2,2'-dipyridyl (0.012 g, 0.046 mmol) in dimethoxy ethane (DME) (5 mL. 10 vol) was purged under a nitrogen atmosphere for 10 min. The reaction mixture was sonicated for 10 minutes, then combined with Solution A. The resulting reaction mixture was degassed with argon and irradiated with a blue LED light (427 nm, Kessil BlueLED) at room temperature for 16 h. Tire progress of the reaction was monitored by TLC using 40 % ethyl acetate in n- hexane. After completion of the reaction, the reaction mixture was poured into saturated sodium bicarbonate (NaHCOs) solution (60 mL) and extracted with dichloromethane (3 X 50 mL). The combined organic layers were dried over anhydrous sodium sulphate (Na2SC>4) and concentrated under reduced pressure. The obtained crude material was purified by reverse phase flash column chromatography on celite bed using 8% acetonitrile in water as eluent. The isolated pure fractions were lyophilized to afford tert-butyl (3- (thicno[2,3-c] pyridin-7-yl) cyclobutyl) carbamate as a mixture of isomers (0.39 g, 55%). LCMS (m / z): 305.1 [M+H]+.

[0332] Step 3. The isolated mixture of isomers of tert-butyl (3-(thieno[2,3-c] pyridin-7-yl) cyclobutyl) carbamate (0.39 g) was submitted to reverse phase preparative HPLC purification for separation of both isomers. (Column: Sunfire Prep C18 (250mm x 19mm x 5pm); Mobile Phase A: 0.05% formic acid in water, Mobile Phase B: 80% acetonitrile in water; Flow rate: 13 mL / min; Gradient: 95% A for 2 mins, 80% A for 35 mins, 0% A for 3 mins, 95% A for 3 mins; Wave Length: 254 nm; RTl(min) 32.5; RT2(min): 37.5; Sample loading: 20 mg; Number Of Runs: 25).

[0333] Eluting fraction 1: Tert-butyl ((ls,3s)-3-(thieno[2,3-c] pyridin-7-yl) cyclobutyl) carbamate (25 mg), off-white solid; LCMS (m / z): 305.1 [M+H]+, 6%. Stereochemistry confirmed by NOE analysis. Eluting fraction 2: Tert-butyl ((lr,3r)-3-(thieno[2,3-c] pyridin-7-yl) cyclobutyl) carbamate (50 mg), off- white solid; LCMS (m / z): 305.1 [M+H]+, 9%. Stereochemistry confirmed by NOE analysis.

[0334] Step 4. To a stirred solution of eluting fraction 1 from step 3 (0.025 g. 0.08 mmol) in dichloromethane (1 mL, 40 vol) was added 4 M hydrochloric acid in 1,4-dioxane (0.25 mL, 10 vol) at 0 °C under an inert atmosphere of nitrogen gas. The resulting mixture stirred at room temperature for 1 h. The107BUSINESS.33535339.1progress of the reaction was monitored by TLC using 10 % methanol in dichloromethane. After completion of reaction, the reaction mixture was concentrated under reduced pressure. The isolated material was triturated with diethyl ether (3 X 7 mL) and dried well under vacuum to afford (ls,3s)-3-(thieno[2,3-c] pyridin-7-yl) cyclobutan-1 -amine hydrochloride (1-57, 0.030 g) as an off-white solid. LCMS (m / z): 205.1 [M+H]+; ’H NMR (400 MHz, DMSO-tL) 5 8.56-8.55 (m, 2H), 8.41 (bs. 2H), 8.16 (s, 1H), 7.82 (d, J= 5.0 Hz, 1H), 4.05-4.00 (m, 1H). 3.89-3.84 (m. 1H), 2.90-2.81 (m, 4H).

[0335] The same procedure was applied to eluting fraction 2 (0.05 g) from step 3 to afford (lr,3r)-3- (thieno[2,3-c] pyridin-7-yl) cyclobutan-1 -amine hydrochloride (1-56, 0.028 g, 83%) as an off-white solid. LCMS (m / z): 205.1 [M+H]+; 'H NMR (400 MHz, DMSO-d6) 8 8.58-8.55 (m, 5H), 8.18 (d, J = 5.0, 1H), 7.84 (d, J= 5.0 Hz, 1H). 4.61 (bs, 1H), 3.91-3.89 (m, 1H), 3.06-3.03 (m, 2H), 2.75-2.68 (m. 2H).

[0336] Additional Exemplary Compounds Prepared via Example Method 11

[0337] Example 12: h5-HT2A Receptor Calcium Assay

[0338] HEK cells over expressing human 5-HT2A receptor were trypsinized, counted, and seeded in black, clear-bottomed 384 well plates at a density of 12,500 cells per well and incubated overnight in media containing 1% dialyzed serum. Next day, media was removed from the cell plates and 30 pl assay buffer (20 mM HEPES: HBSS, pH 7.4) was added. 10 pL Calcium 5 dye solution (Molecular Devices: R8186) was added to the wells and incubated at 37 °C for 40 minutes. Dye solution was made up in 20 mM HEPES: HBSS, pH 7.4 + 2.5 mM probenecid. Compound dilutions (including serial dilutions) were performed in108BUSINESS.33535339.1100% DMSO then transferred to intermediate dilutions for a very limited amount of time (<10 minutes) just before adding to the cell plate. The plates were placed in the FLIPR, after incubation with dye, and fluorescence monitored every 1 second. After 20 seconds 10 pL test compounds and controls were added to the wells and the fluorescence monitored for 5 minutes at ex / em: 488 nm / 510-570 nm in order to monitor compounds as agonists. All compounds were screened in duplicate using a 9 point half-log dose -response curve.

[0339] Data analysis was performed using Dotmatics. Briefly, data was normalized to low (DMSO) and high controls (5-HT Emax)). Assay Z’ should be greater than 0.5, and on-plate control 5-HT should be within 0.25 log of average.

[0340] 115-HT2A Receptor Calcium Assay results are shown in Table 2. The letter codes for pECso include: A (>6): B (>5 - 6); and C (<5). The letter codes for Emax % include: A (>90%); B (90 - >70%): C (70 - >50%); and D (<50%).Table 2. h5-HT2A Receptor Calcium Assay Results109BUSINESS.33535339.1410095-003WQ (221371)

[0341] Example 13: h5-HT2A Receptor NanoBiT I -Arrestin Assay

[0342] HEK cells expressing LgBiT tagged 5-HT2A and smBiT [3- Arrestin are try psinizcd. counted, and seeded in white 384 well plates at a density of 12,500 cells per well and incubated overnight in media containing 1% dialyzed serum. Tire following day 25 pL ofNanoGlo live cell substrate (Promega N2012) is added to each well and the cells incubated for 25 minutes. Compound dilutions (including serial dilutions) are performed in 100% DMSO then transferred to intermediate dilutions for a very limited amount of time (<10 minutes) just before adding to the cell plate. 20 pL of 5X compound solution is added to the cells. Cells are incubated for 90 minutes at 37 °C and luminescence measured using the Envision plate reader. All compounds are screened in duplicate using a 9 point half-log dose -response curve on 2 separate occasions. Data analysis is performed as described in Example 12.

[0343] Example 14: 5-HT2B Receptor Calcium Assay

[0344] HEK cells over expressing human 5-HT2B receptor are trypsinizcd, counted, and seeded in black, clear-bottomed 384 well plates at a density of 12,500 cells per well and incubated overnight in media containing 1% dialysed scrum. Next day, media is removed from cell plates and 30 pL assay buffer (20 mM HEPES: HBSS, pH 7.4) is added. 10 pL Calcium 5 dye solution (Molecular Devices: R8186) is added to the wells and incubated at 37 °C for 40 minutes. Dye solution is made up in 20 mM HEPES: HBSS, pH 7.4 + 2.5 mM probenecid. Compound dilutions (including serial dilutions) are performed in 100% DMSO then transferred to intermediate dilutions for a very limited amount of time (<10 minutes) just before adding to the cell plate. Tire plates are placed in the FLIPR, after incubation with dye, and fluorescence monitored every’ 1 second. After 20 seconds 10 pL test compounds and controls are added to the wells and the 110BUSINESS.33535339.1fluorescence monitored for 5 minutes at ex / em: 488 nm / 510-570 nm in order to monitor compounds as agonists. All compounds are screened in duplicate using a 9 point half-log dose -response curve on 2 separate occasions. Data analysis is performed as described in Example 12.

[0345] Example 15: h5-HT2C Receptor Calcium Assay

[0346] HEK cells over expressing human 5-HT2C receptor are trypsinised, counted and seeded in black, clear-bottomed 384 well plates at a density of 12,500 cells per well and incubated overnight in media containing 1% dialysed serum. Next day, media is removed from cell plates and 30 pL assay buffer (20 mM HEPES: HBSS, pH 7.4) is added. 10 pL Calcium 5 dye solution (Molecular Devices: R8186) is added to the wells and incubated at 37 °C for 40 minutes. Dye solution is made up in 20 mM HEPES: HBSS, pH 7.4 + 2.5 mM probenecid. Compound dilutions (including serial dilutions) are performed in 100% DMSO then transferred to intermediate dilutions for a very limited amount of time (<10 minutes) just before adding to the cell plate. The plates are placed in the FLIPR, after incubation with dye, and fluorescence monitored every 1 second. After 20 seconds 10 pL test compounds and controls are added to the wells and the fluorescence monitored for 5 minutes at ex / em: 488 nm / 510-570 nm in order to monitor compounds as agonists. All compounds are screened in duplicate using a 9 point half-log dose -response curve on 2 separate occasions. Data analysis is performed as described in Example 12.

[0347] Example 16: m5-HT2A Receptor Calcium Assay

[0348] HEK cells over expressing mouse 5-HT2A receptor are trypsinizcd. counted, and seeded in black, clear-bottomed 384 well plates at a density of 12,500 cells per well and incubated overnight in media containing 1% dialysed serum. Next day, media is removed from cell plates and 30 pL assay buffer (20 mM HEPES: HBSS, pH 7.4) is added. 10 pL Calcium 5 dye solution (Molecular Devices: R8186) is added to the wells and incubated at 37 °C for 40 minutes. Dye solution is made up in 20 mM HEPES: HBSS, pH 7.4 + 2.5 mM probenecid. Compound dilutions (including serial dilutions) are performed in 100% DMSO then transferred to intermediate dilutions for a very limited amount of time (<10 minutes) just before adding to the cell plate. Tire plates are placed in the FLIPR, after incubation with dye, and fluorescence monitored every 1 second. After 20 seconds 10 pl test compounds and controls are added to the wells and the fluorescence monitored for 5 minutes at ex / em: 488 nm / 510-570 nm in order to monitor compounds as agonists. All compounds are screened in duplicate using a 9 point half-log dose -response curve on 2 separate occasions. Data analysis is performed as described in Example 12.

[0349] Example 17: Head Twitch Response and Locomotor Activity in mice.

[0350] The aim of this study is to determine the effect of provided compounds to elicit the head twitch response and the effect on locomotor activity. The Head Twitch Response (HTR; also called “wet-dog shakes”) is a widely used behavioral assay in mice and rats respectively to test for activation of the serotonin 5-HT2A receptor. Hie response is a rapid, side-to-side movement of the head and neck. Halberstadt, A. L.,111BUSINESS.33535339.1410095-003WQ (221371)Geyer, M. A. Characterization of the head-twitch response induced by hallucinogens in mice: detection of the behavior based on the dynamics of head movement. Psychopharmacology (Berl). 2013; 227(4):727- 739; Halberstadt, A. L., Geyer, M. A.. Effect of Hallucinogens on Unconditioned Behavior. Curr Top Behov Neurosci. 2018; 36: 159-199. While not a direct correlation, HTR serves as an indicator of potential psychedelic effect in humans. Halberstadt, A. L., Chatha, M., Klein. A. K., Wallach J., Brandt. S. D. Correlation between the potency of hallucinogens in the mouse head-twitch response assay and their behavioral and subjective effects in other species. Neuropharmacology. 2020; 167: 107933. Whole brain and plasma samples are collected for drug metabolism and pharmacokinetics (DMPK).

[0351] Sixty (60) male C57BL / 6J mice (8-9 weeks of age, 20-25 g upon arrival) arc obtained. Mice are dosed with either vehicle (p.o or i.p) or compound (p.o or i.p) at time “0” and placed in the arenas. Dosing is to a timed scheduled. Mice are weighed prior to dosing and body weight recorded. A reference (e.g., lysergic acid diethylamide (LSD) or 2,5-dimethoxy-4-iodoamphetamine (DOI)) may be used.

[0352] Tire number of head twitches are counted by a trained observer who is blind to treatment, and sessions are recorded using video capture equipment (Etho vision vl7) for a period of time post dosing. The locomotor activity of all groups is measured using the Ethovision system. Other behaviours of note are also scored. At the conclusion of the observation period (T=30) each mouse will be humanely euthanized using CO2 and a cardiac puncture performed prior to confirming death via cervical dislocation. The mice are utilized for brain and blood sampling / DMPK.

[0353] Terminal plasma: following confirmation of death, as much blood as possible is removed from the animal to individual K3EDTA tubes, which are then held on wet ice for a maximum of 30 minutes prior to centrifugation. Blood samples are spun at 2000 g for 10 minutes at 4 °C and as much plasma as possible is extracted and transferred to individual 0.5 mL screwcap microtubes, frozen over dry ice and stored at - 80°C for subsequent analysis of compound levels.

[0354] Brain: following confirmation of death, the brain is removed from each mouse, rinsed in purified water, blotted dry. weighed, and snap frozen in individual 7 mL precellys tubes, samples to be stored at -80°C for subsequent analysis of compound levels.

[0355] Data: A square root transformation is used for the number of head twitches. If there is evidence that square root transformed data are not normally distributed, the log(x+l) transformation and no transformation is also considered. The primary analysis is the total number of twitches over the 30-minute observation period. Analysis is by three-way analysis of variance with treatment, day and observer as factors. If an appropriate transformation cannot be found, robust regression may be used. Non-parametric methods (exact Wilcoxon rank sum test) may be used if there are no twitches for many of the animals. Locomotor activity analysis is by two-way AN OVA on square-root transformed data with treatment and day as factors.112BUSINESS.33535339.1410095-003WQ (221371)

[0356] Example 18: Forced Swim Test in mice.

[0357] The experiment is designed to utilize the forced swim test (FST), a method with predictive capabilities for evaluating the efficacy of antidepressant medications. Petit-Demouliere, B , Chenu, F., Bourin, M. Forced swimming test in mice: a review of antidepressant activity. Psychopharmacology (Berl). 2005, 177(3). 245-255: Malikowska-Racia, N._ Salat, K., Nowaczyk. A.. Fijalkowski. L._ Popik, P. Dopamine D2 / D3 receptor agonists attenuate PTSD-like symptoms in mice exposed to single prolonged stress. Neuropharmacology 2019, 155, 1-9; McDonnell, C. W., Dunphy-Doherty, F., Rouine, J., et al. The Antidepressant-Like Effects of a Clinically Relevant Dose of Ketamine Are Accompanied by Biphasic Alterations in Working Memory in the Wistar Kyoto Rat Model of Depression. Front Psychiatry 2021, 11, 599588.

[0358] FST is a utilized behavioral model in preclinical screening, which is based on observing a rodent's response to a threat. Passive behavior, drifting, and lack of movement to attempt escape are interpreted as susceptibility to depressed mood. This test involves placing the animal in a container of water with no means of escape and inducing short-term stress due to the necessity to stay afloat. The assay can provide reproducible results and detect various antidepressants. Cryan J. F., “Depression” Encyclopedia of Behavioral Neuroscience 2010, 382-386. Exposure of animals to the FST has been demonstrated to elicit neurochemical changes in the brain consistent with a depressive phenotype, such as transient reductions in serotonin and norepinephrine levels in cortical and limbic structures. Matthews, K.., Stewart, C., “Depression Models” Encyclopedia of Stress (Second Edition) 2007, 760-766.

[0359] Naive C57BL6 / J mice are used for this study, and a reference (e.g., psilocybin) may be administered. The animals undergo a 7-day acclimatization period to their new environment and are weighed prior to compound administration. To evaluate the efficacy of the tested compounds, the mice are subjected to drug therapy with the vehicle, the tested compounds, and a reference (e.g., psilocybin) at the minimum effective dose (e.g., 5 mg / kg psilocybin). Subsequently, a forced swim test is conducted at certain time points following drug administration (e.g., at 0.5 -2.0 hrs and at 24 hours).

[0360] The mouse is carefully placed in a glass cylindrical tank (approximately 30 cm x 14 cm) filled with water at a temperature of 26-28 °C, ensuring that the water level is high enough to prevent the mouse from touching the bottom with its paws or tail, thus preventing escape . Tire animal is observed and recorded for a duration of 6 minutes after placement in the tank. After recording, the mouse is delicately dried with a soft paper towel and placed back in its cage under a heat lamp for an additional 6 minutes to warm up. Using ANY-maze software, the active swim time, drift time, and attempts to climb the cylinder wall are analyzed based on the last 4 minutes of the recording. A decrease in active swimming time and lack of attempts to escape the cylinder are indicative of depressive-like symptoms.113BUSINESS.33535339.1410095-003WQ (221371)

[0361] Example 19: Chronic Social Defeat Methodology.

[0362] In the first part of the CSD study, CD-I male mice undergo aggression screening (mild) in order to score aggressive behaviour toward C57BL / 6J mice to ensure the defeat of the intruder during chronic social defeat (CSD) procedure. The C57BL / 6J male mice are subjected to 10 days of CSD procedure (moderate) followed by the 1st social preference test.

[0363] 1st social preference test (SP; mild) (day 11) is performed to assess CSD effect on social avoidance, which is the primary behavioural endpoint in the CSD model. The SP test consists of 2 x 2.5 min sessions. During the habituation session, mice explore the apparatus containing an empty perforated cylinder (“no target") placed in one side of tire chamber. Prior to the test session, an unfamiliar CD-I mouse is placed in the perforated cylinder (“target present"). The “interaction zone” is defined as the area surrounding the perforated cylinder. The social preference score is calculated by dividing the time spent in the “interaction zone” when the target is present by the time spent in the “interaction zone” when the target is absent. Tire test assesses the level of social aversion in the mice based on the interaction time of the test mice with the other individual additional parameters: time spent in the comer and total distance travelled are analysed. Based on the results from the first SP test, mice are divided into either exhibiting a stress-resilient (SP score above 100) or a stress- susceptible phenotype (SP score under 100).Subsequently susceptible mice are assigned to experimental groups ensuring that overall average SP scores of each group were at similar level. Following baseline SP recordings mice undergo drug administration with either reference (e.g., psilocybin), vehicle or test compound (TC) on Day 14. At the next step, all groups are submitted to the 2nd SP test (mild) 24 hr post-administration on Day 15 to assess drug effect on social avoidance. Then, all groups are submitted to the 3rd SP test (mild) to assess the long-term drug effect on social avoidance on Day 21 or 28. Body weight and animal welfare are monitored daily.114BUSINESS.33535339.1

Claims

1. CLAIMS1. A compound of formula I” :I” or a pharmaceutically acceptable salt thereof, wherein:X1is N, NRla, or CR1;X2is N or CR2;X3is N or CR3;X is N or CR4;X7is N or CR7;X8is N, C, CH, or C-Ci-g aliphatic;X9is S, N, or NR9a; each — is independently a single or double bond, as valency allows, where one — between X9and X7or X7and X1is a double bond; each of R1, R2, R3. R4. or R7is independently selected from hydrogen, halogen, -CN, -OR’, -NR2, -C(O)R, -C(0)NR2, -C(O)OR, -NRC(O)R, -OC(O)R, or an optionally substituted group selected from C1.6 aliphatic, a 3 - to 8-membered saturated or partially unsaturated carbocyclyl or heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, phenyl, or a 5- to 6-membered heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur;R5is hydrogen or an optionally substituted group selected from Ci-6 aliphatic or 3-to 8-membered saturated or partially unsaturated carbocyclyl or heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; each Rlaand R9ais independently hydrogen or optionally substituted Ci-s aliphatic; each R6is independently hydrogen or optionally substituted Ci-g aliphatic; each R8is independently hydrogen, halogen, -CN, -OR, -NR2, or optionally substituted C1-6 aliphatic; or an R6and an R8group may be taken together to form an optionally substituted 3- to 8-membered saturated or partially unsaturated bridged or fused carbocyclyl or heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or two R8groups on the same atom may be taken together to form an optionally substituted 3- to 8- membered saturated or partially unsaturated spirocarbocyclyl or spiroheterocyclyl having 1-3115BUSINESS.33535339.1heteroatoms independently selected from nitrogen, oxygen, or sulfur: or two R8groups on different atoms may be taken together to form an optionally substituted 3- to 8- membered saturated or partially unsaturated bridged or fused carbocyclyl or heterocyclyl having 1- 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur;R1CIis:Ring A is a saturated or partially unsaturated 4- to 6-membered monocyclic carbocyclyl, a saturated or partially unsaturated 7- to 8-membered bicyclic spirocyclic carbocyclyl. or a saturated or partially unsaturated 4- to 9-membered fused or bridged bicyclic carbocyclyl;Ring B is a saturated or partially unsaturated 4- to 6-membered monocyclic heterocyclyl having one or two nitrogen heteroatoms, a saturated or partially unsaturated 7- to 8-membered bicyclic spirocyclic heterocyclyl having a single nitrogen heteroatom, or a saturated or partially unsaturated 4- to 9- membered fused or bridged bicyclic heterocyclyl having one or two nitrogen heteroatoms;L1is a covalent bond or an optionally substituted bivalent C1-3 saturated or unsaturated, straight or branched, hydrocarbon chain each R is independently hydrogen or optionally substituted Cue aliphatic; and ms 0, 1, 2, 3, 4, 5, 6, 7, or 8.(R8)nThe compound of claim 1, wherein R10isThe compound of claim 2, wherein Ring4. The compound of claim 1, wherein the compound is of formula I”-a:116BUSINESS.33535339.1or a pharmaceutically acceptable salt thereof.The compound of claim 1, wherein R10is6. The compound of claim 5, wherein X8is N.

7. The compound of claim 6, wherein Ring8. The compound of claim 5, wherein X8is C.The compound of claim 1, wherein Ring B isTire compound of claim 8 or 9, wherein Ring117BUSINESS.33535339.

111. The compound of claim 1, wherein the compound is of formula I”-b:or a pharmaceutically acceptable salt thereof.

12. The compound of claim 1, wherein13. The compound of claim 12, wherein R10is, or14. Tire compound of claim 1, wherein the compound is of formula I':118BUSINESS.33535339.1or a pharmaceutically acceptable salt thereof, wherein: each — is independently a single or double bond, as valency allows, where one — is a double bond: each R6and Rsis independently hydrogen or optionally substituted Ci-6 aliphatic; or an R6and an R8group may be taken together to form an optionally substituted 3- to 8-membered saturated or partially unsaturated bridged or fused carbocyclyl or heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or two R8groups on the same atom may be taken together to form an optionally substituted 3- to 8- membered saturated or partially unsaturated spirocarbocyclyl or spiroheterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or two R8groups on different atoms may be taken together to form an optionally substituted 3- to 8- membered saturated or partially unsaturated bridged or fused carbocyclyl or heterocyclyl having 1- 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; andR10is:

15. The compound of claim 1 or 14, wherein the compound is of formulae IX-a, IX-b, IX-c, IX-d, IX- e, or IX-f:119BUSINESS.33535339.1120BUSINESS.33535339.1or a pharmaceutically acceptable salt thereof.

16. The compound of any one of claims 1-15, wherein the compound is of fonnula X:or a pharmaceutically acceptable salt thereof.

17. The compound of any one of claims 1 or 14-16, wherein the compound of fonnula I:or a pharmaceutically acceptable salt thereof.121BUSINESS.33535339.

118. The compound of any one of claims 1 or 14-16, wherein the compound is of formulae I-a, I-b, I- c, I-d, or I-e:I d I-e or a pharmaceutically acceptable salt thereof.

19. Tire compound of any one of claims 1-18, wherein X1is N.122BUSINESS.33535339.

120. The compound of any one of claims 1-18, wherein X1is CR1.

21. Tire compound of anyone of claims 1, 14, or 15, wherein the compound of formulae XI, Xl-a, XI- b, or XI-c:or a pharmaceutically acceptable salt thereof.

22. Tire compound of any one of claims 1-21, wherein X2is N.

23. The compound of any one of claims 1-21. wherein X2is CR2.

24. The compound of any one of claims 1-23, wherein X3is N.

25. Tire compound of any one of claims 1-23, wherein X3is CR3.123BUSINESS.33535339.

126. The compound of any one of claims 1-25, wherein X4is N.

27. Tire compound of any one of claims 1-25, wherein X4is CR4.

28. The compound of any one of claims 1 or 14-18. wherein the compound is of formulae II, Il-a, II- b, II-c, Il-d, or li e:124BUSINESS.33535339.1or a pharmaceutically acceptable salt thereof.

29. The compound of any one of claims 1 or 14-18. wherein the compound is of formulae III, Ill-a,Ill-b, III-c, Ill-d, or Ill-e:125BUSINESS.33535339.1TIT-c126BUSINESS.33535339.1or a pharmaceutically acceptable salt thereof.

30. The compound of any one of claims 1 or 14-18, wherein the compound is of formulae IV, IV-a,IV-b, IV-c, IV-d, or IV-e:127BUSINESS.33535339.1BUSINESS.33535339.

131. The compound of any one of claims 1 or 14-18, wherein the compound is of formulae V, V-a, V- b, V-c, V-d, or V-e:129BUSINESS.33535339.1or a pharmaceutically acceptable salt thereof.

32. The compound of any one of claims 1 or 14-18, wherein the compound is of formulae VI, Vl-a,Vl-b, VI-c, Vl-d, or Vl-e:130BUSINESS.33535339 1or a pharmaceutically acceptable salt thereof.

33. The compound of any one of claims 1 or 14-18. wherein the compound is of formulae VII, Vll-a,131BUSINESS.33535339.1VH-b, VII-c, Vll-d, or Vll-e:VII-c132BUSINESS.33535339.1or a pharmaceutically acceptable salt thereof.

34. The compound of any one of claims 1 or 14-18, wherein the compound is of formulae VIIT, VIIT- a, VUI-b, VIII-c, Vlll-d, or Vlll-e:133BUSINESS.33535339.1or a pharmaceutically acceptable salt thereof.

35. The compound of any one of claims 1, 14, 15, or 21. wherein the compound is of formulae XII,134BUSINESS.33535339.1XH-a, Xll-b, or XII-c:or a pharmaceutically acceptable salt thereof.

36. The compound of any one of claims 1, 14, 15, or 21, wherein the compound is of formulae XIII,XHI-a, XHI-b, or XIII-c:135BUSINESS.33535339.1or a pharmaceutically acceptable salt thereof.

37. The compound of any one of claims 1, 14. or 15, wherein the compound is of formulae XIV, XIV- a, XV, or XV-a:XIV XlV-a136BUSINESS.33535339.1or a pharmaceutically acceptable salt thereof.

38. Tire compound of any one of claims 1-37, wherein each R6is hydrogen.

39. The compound of any one of claims 1-37. wherein each R6is optionally substituted Ci-6 aliphatic.

40. The compound of any one of claims 1-37, wherein each R6is hydrogen or methyl.

41. The compound of any one of claims 1-40, wherein n is 0.

42. The compound of any one of claims 1-37. wherein an R6and an R8group may be taken together to form an optionally substituted 3- to 8-membered saturated or partially unsaturated bridged or fused carbocyclyl or heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

43. The compound of any one of claims 1-37. wherein two R8groups on the same atom may be taken together to form an optionally substituted 3- to 8-membered saturated or partially unsaturated spirocarbocyclyl or spiroheterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

44. The compound of any one of claims 1-37, wherein two R8groups on different atoms may be taken together to form an optionally substituted 3- to 8-membered saturated or partially unsaturated bridged or fused carbocyclyl or heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

45. Tire compound of any one of claim 1-44, wherein R1is hy drogen.137BUSINESS.33535339.

146. The compound of any one of claims 1-44, wherein R1is fluoro, chloro, or bromo.

47. Tire compound of any one of claims 1-44, wherein R1is -CN.

48. The compound of any one of claims 1-44, wherein R1is -OR5.

49. The compound of claim 48, wherein R5is hydrogen or an optionally substituted Ci-e aliphatic.

50. Tire compound of any one of claims 1-44, wherein R1is -NR2.

51. The compound of any one of claims 1-44, wherein R1is -C(O)NR2. -C(O)OR, -NRC(O)R, or - OC(O)R.

52. The compound of any one of claims 1-44, wherein R1is optionally substituted Ci-e aliphatic.

53. The compound of claim 52. wherein R1is C1-6 aliphatic, optionally substituted with halogen or - OR°, wherein R° is hydrogen or C1-6 aliphatic.

54. The compound of any one of claims 1-44, wherein R1is an optionally substituted 3- to 8-membered saturated or partially unsaturated carbocyclyl or heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

55. The compound of any one of claims 1-44, wherein R1is phenyl or an optionally substituted 5- to 6-membered heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

56. The compound of any one of claims 1-44, wherein R1is hydrogen, methyl, ethyl, or -CN.

57. The compound of any one of claim 1-56, wherein R2is hydrogen.

58. The compound of any one of claims 1-56. wherein R2is fluoro, chloro, or bromo.

59. The compound of any one of claims 1-56, wherein R2is -CN.

60. The compound of any one of claims 1-56, wherein R2is -OR5.138BUSINESS.33535339.

161. The compound of claim 60, wherein R5is hydrogen or an optionally substituted Ci-e aliphatic.

62. Tire compound of any one of claims 1-56, wherein R2is -NR2.

63. The compound of any one of claims 1-56, wherein R2is -C(O)NR2. -C(O)OR, -NRC(O)R. or - OC(O)R.

64. Tire compound of any one of claims 1-56, wherein R2is optionally substituted Ci-e aliphatic.

65. The compound of claim 64. wherein R2is Cue aliphatic, optionally substituted with halogen or - OR°, wherein R° is hydrogen or Cue aliphatic.

66. The compound of any one of claims 1-56, wherein R2is an optionally substituted 3- to 8-membered saturated or partially unsaturated carbocyclyl or heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

67. The compound of any one of claims 1-56, wherein R2is phenyl or an optionally substituted 5- to 6-membered heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

68. Tire compound of any one of claims 1-56, wherein R2is hydrogen, methyl, ethyl, or -CN.

69. The compound of any one of claim 1-68, wherein R3is hydrogen.

70. The compound of any one of claims 1 -68, wherein R3is fluoro, chloro, or bromo.

71. Tire compound of any one of claims 1-68, wherein R3is -CN.

72. The compound of any one of claims 1-68. wherein R3is -OR5.

73. The compound of claim 72, wherein R5is hydrogen or an optionally substituted Ci-e aliphatic.

74. Tire compound of any one of claims 1-68, wherein R3is -NR2.139BUSINESS.33535339.

175. The compound of any one of claims 1-68, wherein R3is -C(0)NR2, -C(O)OR, -NRC(O)R, or - OC(O)R.

76. Tire compound of any one of claims 1-68, wherein R3is optionally substituted Ci-e aliphatic.

77. The compound of claim 76. wherein R3is Ci-6 aliphatic, optionally substituted with halogen or - OR°, wherein R° is hydrogen or Ci-6 aliphatic.

78. Tire compound of any one of claims 1-68, wherein R3is an optionally substituted 3- to 8-membered saturated or partially unsaturated carbocyclyl or heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

79. The compound of any one of claims 1-68, wherein R3is phenyl or an optionally substituted 5- to 6-membered heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

80. The compound of any one of claims 1-68, wherein R3is hydrogen, methyl, ethyl, or -CN.

81. The compound of any one of claim 1-80, wherein R4is hydrogen.

82. The compound of any one of claims 1-80, wherein R4is fluoro, chloro, or bromo.

83. The compound of any one of claims 1-80, wherein R4is -CN.

84. The compound of any one of claims 1-80. wherein R4is -OR3.

85. The compound of claim 84, wherein R5is hydrogen or an optionally substituted Ci-6 aliphatic.

86. The compound of any one of claims 1-80, wherein R4is -NR2.

87. The compound of any one of claims 1-80. wherein R4is -C(O)NR2. -C(O)OR, -NRC(O)R. or - OC(O)R.

88. Tire compound of any one of claims 1-80, wherein R4is optionally substituted Ci-e aliphatic.140BUSINESS.33535339.

189. The compound of claim 88, wherein R4is Ci-e aliphatic, optionally substituted with halogen or - OR°, wherein R° is hydrogen or Ci-6 aliphatic.

90. Tire compound of any one of claims 1-80, wherein R4is an optionally substituted 3- to 8-membered saturated or partially unsaturated carbocyclyl or heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

91. The compound of any one of claims 1-80, wherein R4is phenyl or an optionally substituted 5- to 6-membered heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

92. The compound of any one of claims 1-80. wherein R4is hydrogen, methyl, ethyl, or -CN.

93. The compound of any one of claim 1-92, wherein R7is hydrogen.

94. Tire compound of any one of claims 1-92, wherein R7is fluoro, chloro, or bromo.

95. The compound of any one of claims 1-92. wherein R7is -CN.

96. The compound of any one of claims 1-92, wherein R7is -OR5.

97. Tire compound of claim 96, wherein R5is hydrogen or an optionally substituted Ci-e aliphatic.

98. The compound of any one of claims 1-92. wherein R7is -NR2.

99. The compound of any one of claims 1-92, wherein R7is -C(O)NR2, -C(O)OR, -NRC(O)R, or - OC(O)R.

100. The compound of any one of claims 1-92, wherein R7is optionally substituted C1-6 aliphatic.

101. The compound of claim 100, wherein R7is C1-6 aliphatic, optionally substituted with halogen or - OR°, wherein R° is hydrogen or C1-6 aliphatic.141BUSINESS.33535339.1102. The compound of any one of claims 1-92, wherein R7is an optionally substituted 3- to 8-membered saturated or partially unsaturated carbocyclyl or heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

103. The compound of any one of claims 1-92, wherein R7is phenyl or an optionally substituted 5- to 6-membered heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

104. The compound of any one of claims 1-92, wherein R7is hydrogen, methyl, ethyl, or -CN.

105. Tire compound of claim 1, wherein the compound is of Table 1, or a pharmaceutically acceptable salt thereof.

106. A pharmaceutical composition comprising a compound of any one of claims 1-105, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, adjuvant, or vehicle.

107. Amethod of activating 5-HT2AR, or a mutant thereof, in a biological sample comprising contacting said biological sample with a compound of any one of claims 1-105, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 106.

108. A method of selectively activating 5-HT2AR, or a mutant thereof, (e.g., over the 5-HT2B and / or 5-HT2C receptors, or mutants thereof) in a biological sample comprising contacting said biological sample with a compound of any one of claims 1-105, or a pharmacally acceptable salt thereof, or a pharmacal composition of claim 106.

109. A method of increasing activation of a G protein signaling pathway associated with 5-HT2AR over a 0-arrestin signaling pathway associated with 5-HT2AR in a biological sample, comprising administering to the biological sample a compound of any one of claims 1-105, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 106.

110. A method of activating 5-HT2AR, or a mutant thereof, in a patient comprising administering a compound of any one of claims 1-105, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 106.142BUSINESS.33535339.1111. A method of selectively activating 5-HT2AR, or a mutant thereof, (e.g., over the 5-HT2B and / or 5-HT2C receptors, or mutants thereof) in a patient comprising administering a compound of any one of claims 1-105, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 106.

112. A method of increasing activation of a G protein signaling pathway associated with 5-HT2AR over a P-arrestin signaling pathway associated with 5-HT2AR in a patient in need thereof, comprising administering to the patient a compound of any one of claims 1-105, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 106.

113. A method for treating a 5-HT2AR-mediated disorder comprising administering to a patient a compound of any one of claims 1-105, or a pharmaceutically acceptable salt thereof, or a pharmacal composition of claim 106.

114. A method for treating a neurological disease, disorder, or condition comprising administering to a patient a compound of any one of claims 1-105, or a pharmaceutically acceptable salt thereof, or a pharmacal composition of claim 106.

115. The method of claim 114. wherein neurological disease, disorder, or condition is depression, anxiety, substance abuse, and headaches.

116. Tire method of any one of claims 110-115, wherein tire patient does not experience a hallucinogenic effect as a result of the activating or treating.143BUSINESS.33535339.1

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